Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

ABSTRACT

Provided is a compound of formula (I), in which Ar 1 , R 1 , U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a U.S. National Stage Application ofPCT/US2015/067895 filed Dec. 29, 2015, which claims priority to and thebenefit of U.S. Provisional Application 62/097,226 filed on Dec. 29,2014, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under HHSN261200800001E,R01 CA051497, and NCI CA51497 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND

Agents that target enzymes involved in cancer cell metabolism offer anattractive therapeutic route in view of the potential to preferentiallytarget cancer tissue over normal tissue. While normal tissue typicallyuses glycolysis only when the oxygen supply is low, cancer tissue reliesheavily on aerobic glycolysis regardless of the oxygen supply level.This property is known as the Warburg effect (Vander Heiden et al.,Science, 2009, 324(5930): 1029-1033). Lactate dehydrogenase (LDH) isinvolved in the final step of glycolysis, in which pyruvate is convertedto lactate. The decrease in the rate of pyruvate entering the TCA(tricarboxylic acid) cycle and the concurrent increase in lactateproduction is vital for the growth and survival of tumors. There are twodifferent subunits of LDH, LDHA and LDHB, but both subunits have thesame active site and catalyze the conversion of pyruvate to lactate. Incancer patients, serum total lactate dehydrogenase (LDHS, a tetramer ofLDHA sub-units; the maj or LDH isoenzyme involved in glycolysis) levelsare often increased, and the gene for LDHA, is up-regulated. Tumor cellscan then metabolize lactate as an energy source. Inhibition of LDHresults in the stimulation of mitochondrial respiration as acompensatory mechanism. LDH inhibition is expected to reduce the abilityof the cell to effectively metabolize glucose and reduce tumor cellproliferation and tumor growth. Thus, compounds that inhibit LDHactivity have potential for the development of anti-cancer therapeutics.

LDHA inhibitors have been known previously. For example, gossypol is anonselective inhibitor of LDH that blocks the binding of NADH, with aK_(i) for LDHA and lactate dehydrogenase B (LDHB) of 1.9 and 1.4 μM,respectively (Doherty et al., J. Clin. Invest., 2013, 123(9):3685-3692). Billiard et al. (Cancer and Metabolism, 2013, 1(19): 1-17)reports that certain derivatives of3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl)amino) benzoic acid are potent inhibitors of LDH and were 10- to 80-foldmore selective for LDHA inhibition than LDHB inhibition. However, the invivo bioavailability of the inhibitors was found to be poor.

In view of the foregoing, there remains a need to provide novel LDHinhibitors with improved potency, selectivity, and/or bioavailabilityfor the treatment of cancer.

SUMMARY

The present invention provides a compound of formula (I)

in which Ar¹, R¹, U, V, W, X, and p are as described herein. It has beendiscovered that a compound defined by formula (I) is effective ininhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B(LDHB) activity, thereby making the compound effective in treatingcancer. It has also been discovered that inhibitors of LDHA and/or LDHBare useful for treating fibrosis, including idiopathic pulmonaryfibrosis. It is envisioned that a compound of formula (I) is desirablefor treating cancer because the compound tends to be selective for LDHAand/or LDHB relative to other dehydrogenases (e.g., GAPDH and PHGDH)and/or have a desired solubility, permeability, and/or pharmacokineticsprofile (e.g., ADME) for an anti-cancer agent.

Thus, the disclosure further provides a method of treating cancer in apatient comprising administering to the patient an effective amount ofthe compound of formula (I) or a prodrug or a pharmaceuticallyacceptable salt thereof.

In another embodiment the disclosure provides a method of treatingfibrosis, including idiopathic pulmonary fibrosis, in a patientcomprising administering to the patient an effective amount of thecompound of formula (I) or a prodrug or a pharmaceutically acceptablesalt thereof.

Also provided is a method of treating a patient with cancer cellsresistant to an anti-cancer agent, comprising administering to thepatient an effective amount of the compound of formula (I) or a prodrugor a pharmaceutically acceptable salt thereof, and the anti-canceragent, whereby the compound, prodrug, or pharmaceutically acceptablesalt thereof re-sensitizes the cancer cells to the anti-cancer agent.

The invention provides a method of inhibiting lactate dehydrogenase A(LDHA) and/or lactate dehydrogenase B activity in a cell comprisingadministering a compound of formula (I) or a prodrug or apharmaceutically acceptable salt thereof to a cell.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

Ar¹ is an optionally substituted moiety comprising at least one 5- or6-membered monocyclic heteroaryl that contains one, two, or threeheteroatoms selected from nitrogen, oxygen, and sulfur;

U is aryl, —C(O)aryl, Het, or —C(O)Het, each of which is optionallysubstituted, wherein Het is a monocyclic or bicyclic moiety comprising aheterocycloalkyl that contains at least two double bonds and one, two,or three heteroatoms selected from nitrogen, oxygen, and sulfur;

R¹ is independently chosen from halo, —CO₂R⁴, —C(O)NR⁵R⁶,—(C₁-C₈hydrocarbyl), —C(O)NHOH, —(C₀-C₄hydrocarbyl)((mono- or bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —C(O)O—(C₀-C₄hydrocarbyl)(mono- or bicyclic heterocycle having 1to 4 heteroatoms independently chosen from N, O, and S), —P(O)(OH)₂,—SO₂(OH), —B(OR¹³)(OR¹⁴), —C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹except halo is substituted or unsubstituted;

R² is independently chosen from hydroxyl, halo, —CN, —NO₂,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₅cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹except halo is substituted or unsubstituted;

V is aryl, heteroaryl, or heterocycloalkyl, each of which is substitutedwith —(R²)_(n), wherein the heteroaryl or heterocycloalkyl is a 5- or6-membered monocyclic moiety that contains one, two, or threeheteroatoms selected from nitrogen, oxygen, and sulfur;

W is —(R³)_(m) or

R² is independently chosen from hydroxyl, halo, —CN, —NO₂,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)—NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, —SF₅,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or when W is phenyl, then two R³ moieties and the phenylgroup to which they are attached form a naphthyl group that isoptionally substituted with at least one additional R³ moiety;

each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or different and each ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂aryl,heteroaryl, or heterocycloalkyl;

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring;

X is a bond, —CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O), —O—, —SO—,—SO₂—, or —S—;

m, n, and q are the same or different and each is 0 or an integer from1-5; and

p is 0, 1, or 2;

provided

when Ar¹ is quinolinyl, then U is not pyrimidinyl;

when Ar¹—U is 2-(1H-indol-1-yl)thiazolyl, then X at the 3-position onthe indolyl group is not a bond or —CH₂—, or W at the 3-position on theindolyl group is not phenyl, or R³ at the 3-position on the indolylgroup is not benzyl; and

when Ar¹—U is 2-(1H-pyrazol-1-yl)thiazolyl, then W at the 3-position onthe pyrazolyl group is not 4-trifluoromethylphenyl or 4-nitrophenyl, orX at the 4-position on the pyrazolyl group is not a bond,

or a prodrug or pharmaceutically acceptable salt thereof.

In an aspect, Ar¹ is indolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, quinolinyl,indazolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, thiofuranyl,pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of whichis optionally substituted. When Ar¹ is substituted, there can be 1 to 3substituents (e.g., 1, 2, or 3 substituents) that are the same ordifferent. Suitable substituents include, e.g., C₁-C₈alkyl,C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkylalkyl,hydroxyl, C₁-C₈ alkoxy, C₃-C₆cycloalkyloxy, C₁-C₈haloalkoxy,C₁-C₈haloalkyl, halo, —CN, cyanoalkyl, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵(SO₂)R⁴, —NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴, aryl,heteroaryl, and/or heterocycloalkyl.

In certain compounds, Ar¹ is pyrazolyl, indolyl, orpyrrolo[2,3-b]pyridinyl, each of which is optionally substituted. Forexample, Ar¹ can be pyrazolyl or indolyl substituted with a substituent,such as, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, hydroxyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy,C₁-C₈haloalkoxy, C₁-C₈ haloalkyl, halo, —CN, cyanoalkyl, —NO₂, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴, —NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR′R⁶,—SO₂R⁴, aryl, arylalkyl, heteroaryl, heteroarylalkyl, orheterocycloalkyl. The pyrazolyl can be substituted with C₁-C₈ alkyl,cyclopropyl, —CH₂-cyclopropyl, —CH═CH₂, —C≡C-cyclopropyl, —OH, —CO₂H,C₁-C₈ alkoxy, CF₃, Cl, F, I, —CN, —CH₂CN, NH₂, —C(O)NH₂, —NH-pyridinyl,—CH₂-tetrazolyl, phenyl, benzyl, or —SO₂Me.

In any of the foregoing embodiments, U is phenyl, —C(O)phenyl, indolyl,imidazolyl, oxazolyl, thiazolyl, furanyl, thiofuranyl, pyrrolyl,pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or6-oxo-1,6-dihydropyridazin-3-yl, each of which is optionallysubstituted.

In other aspects, U is Het or —C(O)Het, and Het is

wherein R⁵ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl,aryl, heteroaryl, or heterocycloalkyl, each of these Het moieties isoptionally substituted, and each point of attachment can be either Ar¹or R¹.

In an embodiment, U is

each of which is optionally substituted, and wherein each point ofattachment can be either Ar¹ or

When U is substituted, there can be 1 or 2 substituents that are thesame or different. Suitable substituents include, e.g., C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl,hydroxyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, C₁-C₈ haloalkoxy, C₁-C₈haloalkyl, halo, —CN, cyanoalkyl, —NO₂, CO₂R⁴, C(O)NR⁵R⁶, NR⁵(SO₂)R⁴,NR⁵C(O)R⁴, NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO²R⁴, aryl, arylalkyl,heteroaryl, and/or heterocycloalkyl.

In a certain embodiment of a compound of formula (I), Ar¹ is pyrazolyl,indolyl, or pyrrolo[2,3-b]pyridinyl, each of which is optionallysubstituted, and U is

each of which is optionally substituted. In this embodiment, thefollowing core structures of formula (I) can be formed:

in which X² is —NR⁵—, —O—, or —S—; p is 0; 1 or 2; and R¹ is halo,—CO₂R⁴, —C(O)NR⁵R⁶, —CH₂OH, —CHCF₃OH, —C(CF₃)₂OH,—C(O)NHOH—C(O)OCR⁵R⁶OC(O)OR⁴, —C(O)O-2,3-dihydro-1H-indenyl,—C(O)O-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,1,3,4-oxadiazol-2(3H)-one, isoxazol-3(2H)-one, —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —SO₂NR⁵R⁶, or tetrazolyl.

In any of the foregoing embodiments, R¹ is —CO₂H or —CO₂(C₁-C₈ alkyl),wherein the C₁-C₈ alkyl is substituted or unsubstituted, or a prodrug ora pharmaceutically acceptable salt thereof.

In any of the foregoing embodiments, V is phenyl, piperazinyl,pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiophenyl,morpholinyl, pyridinyl, pyridazinyl, pyrimidyl, or pyrazinyl, each ofwhich is substituted with —(R²)_(n). In some aspects, V is phenylsubstituted with —(R²)_(n).

In any of the foregoing embodiments, R² is —SO₂NR⁵R⁶; and R⁵ and R⁶ arethe same or different and each is H or C₁-C₈ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl, or ten-butyl). In some aspects,R² is —SO₂NH₂.

In any of the foregoing embodiments, n is 1, so that V ismonosubstituted.

In any of the foregoing embodiments, W is

In any of the foregoing embodiments, R³ is independently halo,C₁-C₈haloalkyl, C₁-C₈haloalkoxy, substituted or unsubstitutedC₁-C₄alkyl, or substituted or unsubstituted phenyl.

In any of the foregoing embodiments, m is 1 or 2.

In any of the foregoing embodiments, X is —CR⁸R⁹— (e.g., —CH₂—), —O—, or—NH—, in which R⁸ and R⁹ are the same or different and each is hydrogen,C₁-C₈alkyl, C₂-C₈alkenyl, C₃-C₆cycloalkyl, or aryl.

In some aspects, the compound of formula (I) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ia)

wherein

Y¹, Y², Y³, Y⁴, and Y⁵ are each independently CH or N;

R¹ is independently chosen from halo, —C(O)R⁴, —CH₂OH, —C(O)NHCN,—C(O)NHSO₂H, —C(S)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —(C₁-C₈hydrocarbyl),—C(O)NHOH, —C(O)OCR⁵R⁶OC(O)OR⁴, —(C₀-C₄hydrocarbyl)((mono- or bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —C(O)O—(C₀-C₄hydrocarbyl)(mono- or bicyclic heterocycle having 1to 4 heteroatoms independently chosen from N, O, and S), —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹except halo is substituted or unsubstituted;

R² is independently chosen from hydroxyl, halo, —CN, —NO₂,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, —SF₅,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or two R³ moieties and the phenyl group to which they areattached form a naphthyl group or its heterocyclic analog that isoptionally substituted;

each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or different and each ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl;

R¹⁰ is hydrogen, halo, —CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴,—NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴, C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁰except hydrogen, halo. —CN, and —NO₂ is substituted or unsubstituted;

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring;

X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O)—, —O—, or—S—;

X² is —NR⁵—, —O—, —CO—, —SO₂—, or —S—;

m, n, and q are the same or different and each is 0 or an integer from1-5; and

p is 1 or 2.

In an embodiment of formula (Ia),

R¹ is independently chosen from halo, —CO₂R⁴, —CONH₂, —C(O)NHOH,—P(O)(OH)₂, —B(OR¹³)(OR¹⁴), —SO₂(OH), —SO₂NR⁵R⁶, —(C₁-C₈alkylene)OH,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, heteroaryl,and —C(O)O— heteroaryl, each of which R¹ except hydrogen, halo,—P(O)(OH)₂, —CONH₂, and —SO₂(OH), is substituted or unsubstituted;

each R⁴, R⁵, and R⁶ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, heteroaryl, orheterocycloalkyl, each of which R⁴, R⁵, and R⁶ except H is substitutedor unsubstituted;

R² is independently chosen from hydroxyl, halo, —CN, —NO₂, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₁-C₈ alkoxy, —O—C₃-C₆cycloalkyl,C₆-C₁₂ aryl, —O—C₆-C₁₂ aryloxy, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl,—(CH₂)_(q)heterocycloalkyl, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴,—(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶,—(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, and —(CH₂)_(q)SO₂R⁴, each of whichR² except hydrogen, hydroxyl, halo, —CN, —NO₂, SF₅, is substituted orunsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, SF₅, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ alkenynyl, C₁-C₈alkoxy,—(CH₂)₄C₃-C₈cycloalkyl, —O(CH₂)_(q)C₃-C₈cycloalkyl,—(CH₂)_(q)C₃-C₈cycloalkenyl, —(C₂-C₄alkynyl)(C₃-C₆cycloalkenyl),—(CH₂)_(q)C₆-C₁₂aryl, —O(CH₂)_(q)C₆-C₁₂aryl, —(CH₂)_(q)heteroaryl,—O(CH₂)_(q)heteroaryl, —(C₂-C₄alkenyl)heteroaryl,—(C₂-C₄alkynyl)heteroaryl, —(CH₂)_(q)heterocycloalkenyl,—O(CH₂)_(q)(heterocyloalkenyl, —(C₂-C₄alkenyl)heterocycloalkenyl,—(C₂-C₄alkynyl)heterocycloalkenyl, —(CH₂)_(q)heterocycloalkyl,—O(CH₂)_(q)heterocycloalkyl, —(C₂-C₄alkenyl)heterocycloalkyl, and—(C₂-C₄alkynyl)heterocycloalkyl, each of which R³ except hydrogen,hydroxyl, halo, —CN, —NO₂, and SF₅ is substituted or unsubstituted;

R¹⁰ is hydrogen, —CN, hydroxyl, halo, C₁-C₈alkyl, C₂-C₈alkenyl,C₂-C₈alkynyl, C₁-C₆alkoxy, —(C₀-C₂alkyl)NR⁵R⁶,—(C₀-C₂alkyl)C₃-C₆cycloalkyl, —C≡C(C₃-C₆cycloalkyl) —(C₀-C₂alkyl)C₆-C₁₂aryl, —(C₀-C₂alkyl)heterocycloalkyl, or —(C₀-C₂alkyl)heteroaryl, each ofwhich R¹⁰ except hydrogen, hydroxyl, and halo is substituted orunsubstituted; and

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring.

In another embodiment of formula (Ia),

R¹ is independently chosen from halo, hydroxyl, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, —CO₂R⁴, —CH₂OH, —CHCF₃OH, —C(CF₃)₂OH, —C(O)NHOH,—P(O)(OH)₂, —B(OR¹³)(OR¹⁴), —SO₂(OH), —SO₂NR⁵R⁶,—C(O)O-2,3-dihydro-1H-indenyl,—C(O)O-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,1,3,4-oxadiazol-2(3H)-one, isoxazol-3(2H)-one, and tetrazolyl, each ofwhich R¹ except hydrogen, halo is substituted or unsubstituted;

R² is independently chosen from halo and —(CH₂)_(q)SO₂NR⁵R⁶, where oneof R² is —(CH₂)_(q)SO₂NR⁵R⁶;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, SF₅, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ alkenynyl, C₁-C₈alkoxy,

—(CH₂)_(q)C₃-C₈cycloalkyl, —O(CH₂)_(q)C₃-C₆cycloalkyl,—(CH₂)_(q)C₃-C₆cycloalkenyl, —(C₂-C₄alkynyl)(C₃-C₆cycloalkenyl),

—(CH₂)_(q)C₆-C₁₂phenyl, —O(CH₂)_(q)C₆-C₁₂phenyl,

—(CH₂)_(q)heteroaryl, —O(CH₂)_(q)heteroaryl, —(C₂-C₄alkenyl)heteroaryl,and —(C₂-C₄alkynyl)heteroaryl, where the heteroaryl group is a oxazolyl,thienyl, thiazolyl, furanyl, pyrazolyl, and imidazolyl group;

—(CH₂)_(q)heterocycloalkenyl, —O(CH₂)_(q)(heterocyloalkenyl,—(C₂-C₄alkenyl)heterocycloalkenyl, —(C₂-C₄alkynyl)heterocycloalkenyl,where the heterocycloalkenyl is dihydropyranyl, dihydrofuranyl,dihydrothiopyranyl, and dihydropyridinyl,

—(CH₂)_(q)heterocycloalkyl, —O(CH₂)_(q)heterocycloalkyl,—(C₂-C₄alkenyl)heterocycloalkyl, —(C₂-C₄alkynyl)heterocycloalkyl, wherethe heterocycloalkyl is tetrahydropyranyl, tetrahydrofuranyl,piperazinyl, piperidinyl, and pyrrolidinyl, each of which R³ excepthydrogen, hydroxyl, halo, —CN, —NO₂, and SF₅ is substituted orunsubstituted;

each R⁴, R⁵, and R⁶ is the same or different and each is H or C₁-C₈alkyl, wherein C₁-C₈ alkyl is substituted or unsubstituted;

R¹⁰ is hydrogen, —OH, halo, —CH₂OH, —CN, —CH₂CN, —NH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₁-C₄alkoxy, C₁-C₂haloalkyl. C₁-C₂haloalkoxy, —(C₀-C₃alkyl)-cyclopropyl, —(C₀-C₃ alkyl)-cyclobutyl, —C≡C-cyclopropyl,—C≡C-cyclobutyl phenyl, benzyl, or —CH₂-tetrazolyl, each of whichcyclopropyl, —(C₁-C₃ alkyl)-cyclopropyl, —CH═CH₂, —C≡C-cyclopropyl,phenyl, or benzyl is substituted or unsubstituted; and

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring.

In yet another embodiment of formula (Ia),

R¹ is independently chosen from hydroxyl, halo, —CO₂H, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂haloalkyl optionally substituted with halo,C₁-C₂haloalkoxy, and —CO₂(C₁-C₆ alkyl),

R² is chosen from F and —SO₂NH₂, where one of R² is —SO₂NH₂;

R³ is independently chosen from

(a) halogen, hydroxyl, SF₅;

(b) C₁-C₆hydrocarbyl where any alkylene (CH₂) group in the hydrocarbylchain is optionally replaced with NH, O, or S;

(c) —C₀-C₂hydrocarbyl (phenyl), —C₀-C₂hydrocarbyl (phenyl),—C₀-C₂hydrocarbyl (thiophenyl), —C₀-C₂hydrocarbyl (oxazolyl),—C₀-C₂hydrocarbyl(thiazolyl), —C₀-C₂hydrocarbyl (tetrahydrofuranyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkyl), —C₀-C₂hydrocarbyl(C₃-C₆cycloalkyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkanyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkenyl), —C₀-C₂hydrocarbyl(tetrahydropyrenyl), —C₀-C₂hydrocarbyl (imidazolyl),—C₀-C₂hydrocarbyl(thiophenyl), where any alkylene (CH₂) group in theC₀-C₂hydrocarbyl chain is optionally replaced with NH, O, or S;

where each of (b) is unsubstituted or substituted with 1 or moresubstituents independently chosen from halogen, hydroxyl, cyano, amino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

where each of (c) is unsubstituted or substituted with 1 or moresubstituents independently chosen from halogen, hydroxyl, cyano, amino,C₁-C₄alkyl, C₁-C₆cycloalkyl, mono- or di-C₁-C₄alkylamino, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy

In some aspects, the compound of formula (I) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ib)

wherein

R¹ is independently chosen from halo, —CO₂R⁴, —C(O)NR⁵R⁶,—(C₁-C₈hydrocarbyl), —C(O)NHOH, —C(O)OCR⁵R⁶OC(O)OR⁴, —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹except halo is substituted or unsubstituted;

R² is independently chosen from hydroxyl, halo, —CN, —NO₂,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, —SF₅,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or

each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or different and each ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, each of which C₁-C₈ alkyl, C₂-C₈alkenyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, or heterocycloalkyl issubstituted or unsubstituted;

R¹⁰ is hydrogen, halo, —CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴,—NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR′R⁶, —SO₂R⁴, C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁰except hydrogen, halo. —CN, and —NO₂ is substituted or unsubstituted;

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring;

X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O)—, —O—, —CO—,—SO₂—, or —S—;

X² is —NR⁵—, —O—, —SO—, or —SO₂—, or —S—;

X³ is CH or N;

m, n, and q are the same or different and each is 0 or an integer from1-5; and

p is 1 or 2.

In some aspects, the compound of formula (I) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ic)

wherein

R¹ is independently chosen from halo, —CO₂R⁴, —C(O)NR⁵R⁶,—(C₁-C₈hydrocarbyl), —C(O)NHOH, —P(O)(OH)₂, —B(OR¹³)(OR¹⁴), —SO₂(OH),—C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹ except halo issubstituted or unsubstituted;

R² is independently chosen from hydroxyl, halo, —CN, —NO₂,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, —SF₅,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted;

each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or different and each ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl;

R¹⁰ is hydrogen, halo, —CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴,—NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴, C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁰except hydrogen, halo. —CN, and —NO₂ is substituted or unsubstituted;

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring;

ring Cy is substituted or unsubstituted C₃-C₆ cycloalkyl,

X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O)—, —O—, —CO—,—SO—, —SO₂—, or —S—;

X² is —NR⁵—, —O—, —SO₂—, or —S—;

m, n, and q are the same or different and each is 0 or an integer from1-5; and

p is 1 or 2.

In some aspects, the compound of formula (I) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Id)

wherein

R¹ is independently chosen from halo, —CO₂R⁴, —C(O)NR⁵R⁶,—(C₁-C₈hydrocarbyl), —C(O)NHOH, —(C₀-C₄hydrocarbyl)((mono- or bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —C(O)O—(C₀-C₄hydrocarbyl)(mono- or bicyclic heterocycle having 1to 4 heteroatoms independently chosen from N, O, and S), —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —SO₂NR⁵R⁶, each of which R¹ except halo issubstituted or unsubstituted;

R³ is independently chosen from hydroxyl, halo, —CN, —NO₂, —SF₅,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or

two R³ moieties and the phenyl group to which they are attached form anaphthyl group or its heterocyclic analog that is optionallysubstituted;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂aryl,C₁-C₁₂heteroaryl, or C₁-C₁₂heterocycloalkyl, each of which C₁-C₈ alkyl,C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂aryl, C₁-C₁₂heteroaryl, orC₁-C₁₂heterocycloalkyl is substituted or unsubstituted;

R¹⁰ is hydrogen, halo, —CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴,—NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴, C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁶except hydrogen, halo, —CN, and —NO₂ is substituted or unsubstituted;

each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring;

X² is —NR⁵—, —O—, —SO—, —SO₂—, or —S—;

m and q are the same or different and each is 0 or an integer from 1-5;and

p is 1 or 2.

In any of the foregoing embodiments of formula (Ia)-(Id), R¹⁰ ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, aryl, arylalkyl, hydroxyl, hydroxyalkyl, halo,C₁-C₈ haloalkyl, —CN, cyanoalkyl, —NR⁵R⁶, or heteroarylalkyl. In anaspect, R¹⁰ is hydrogen, C₁-C₈ alkyl, —CH═CH₂, cyclopropyl,—C≡C-cyclopropyl, —OH, —CH₂OH, —CF₃, —CF₂CF₃, —Cl, —F, —I, —CN, —CH₂CN,—NH₂, phenyl, benzyl, or —CH₂-tetrazolyl.

In any of the foregoing embodiments of formula (Ia)-(Id), R¹ is —CO₂H orsubstituted or unsubstituted CO₂(C₁-C₈ alkyl) or a prodrug or apharmaceutically acceptable salt thereof. In an aspect of thisembodiment, p is 1.

In any of the foregoing embodiments of formula (Ia)-(Ic), R² is—SO₂NR⁵R⁶; and R⁵ and R⁶ are the same or different and each is hydrogenor substituted or unsubstituted C₁-C₈ alkyl.

In any of the foregoing embodiments of formula (Ia)-(Ic), n is 1.

In any of the foregoing embodiments of formula (Ia)-(Id), R³ ishydrogen, halo, substituted or unsubstituted C₁-C₈ haloalkyl,substituted or unsubstituted C₁-C₈ haloalkoxy, or substituted orunsubstituted aryl.

In any of the foregoing embodiments of formula (Ia)-(Id), m is 1 or 2.

In any of the foregoing embodiments of formula (Ia)-(Ic), X¹ is —CR⁸R⁹—(e.g., —CH₂—), —O—, or —NH—, in which R⁸ and R⁹ are the same ordifferent and each is hydrogen, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₃-C₆ cycloalkyl, or substituted or unsubstituted aryl.

In any of the foregoing embodiments of formula (Ia)-(Id), X² is —S—.

In any of the foregoing embodiments of the compound of formula (Ib), X³is —CH—.

In an aspect, the compound of formula (Ia) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ia-1):

wherein

R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which is substituted orunsubstituted;

R^(b) and R^(e) are the same or different and each is H or substitutedor unsubstituted C₁-C₈ alkyl;

each R² is the same or different and is independently chosen fromhydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₁-C₈ alkoxy,C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl,haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, and—(CH₂)₄heterocycloalkyl, each of which R² except hydroxyl and halo issubstituted or unsubstituted;

R³ is independently chosen from hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₆ cycloalkyl, —(C₁-C₄hydrocarbyl)C₃-C₆ cycloalkyl,C₁-C₈ alkoxy, —(C₀-C₄alkoxy)C₃-C₆cycloalkyl, —(C₀-C₄alkoxy)aryl, halo,C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂,—C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(C₀-C₄hydrocarbyl)aryl,—(C₀-C₄hydrocarbyl)heteroaryl, —(C₀-C₄alkoxy)heteroaryl,—(C₀-C₄alkoxy)heterocycloalkyl, and —(C₀-C₄hydrocarbyl)heterocycloalkyl, each of which R³ except hydroxyl and halo issubstituted or unsubstituted; or

two R³ moieties and the phenyl group to which they are attached form anaphthyl group that is optionally substituted;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen,C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of which C₁-C₈ alkyl and C₃-C₆cycloalkyl is substituted or unsubstituted;

R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, aryl, arylalkyl,heteroarylalkyl, or —SO₂R⁴, each of which R¹⁰ except hydrogen, hydroxyland halo is substituted or unsubstituted;

X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —O—, —S(O)—, or —S(O)₂—, or —S—;

n is an integer from 0 to 4; and

m and q are the same or different and each is 0 or an integer from 1-5.

In an embodiment, compound of formula (Ia-1) comprise R^(a) is hydroxylor —O(C₁-C₈ alkyl); R^(b) and R^(c) are H; R² is hydrogen; R³ is halo,aryl, or haloaryl (e.g., halo or phenyl); or two R³ moieties and thephenyl group to which they are attached form a naphthyl group that isoptionally substituted; R¹⁰ is hydrogen, C₁-C₈ alkyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂CH₂cyclopropyl, cyclobutyl, —CH₂-cyclobutyl,—CH═CH₂, —C≡C-cyclopropyl, phenyl, benzyl, —I, —CF₃, —NH₂, or —CN; andX¹ is —CH₂— or —NH—; and m is 0, 1, or 2.

In an embodiment, the disclosure includes compounds and salts of formula(Ia-1), wherein

R^(a) is R⁴, —OR⁴, or —NR⁵R⁶;

R² is one or more substituents independently chosen from halo, hydroxyl,—CN, —NO₂, amino, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, C₁-C₂ alkyl,C₁-C₂ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy;

each R⁴, R⁵, and R⁶, is the same or different and each is hydrogen orC₁-C₂ alkyl; and

R¹⁰ is hydrogen, hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl,C₁-C₄ alkoxy, C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴.

In an embodiment the disclosure also includes compounds and salts offormula (Ia-1) wherein:

one of R³ is selected from C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is chosen from thienyl, furanyl, thiazolyl, pyrazolyl,imidazolyl; each of which one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy; and 0 or 1 or more R³ is selected from hydroxyl, halo,—CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy.

In an aspect, a compound of formula (Ia-1) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ia-2):

Wherein

Y═—CH═CH—, O, S, NH;

R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R^(4′) R⁵, and R⁶ issubstituted or unsubstituted;

each R² is the same or different and each is hydrogen, hydroxyl, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, C₁-C₈alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which R² except hydrogen, hydroxyland halo is substituted or unsubstituted;

Each R¹¹ and R¹² are independently selected from hydroxyl, halo, —CN,NO₂, C₁-C₈ alkyl, C₂-C₈ alkenylC₁-C₈ alkoxy, C₁-C₂ haloalkoxy, C₁-C₂haloalkyl, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴,—(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶,—(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, and —(CH₂)_(q)SO₂R⁴, each of whichR¹¹ and R¹² other than hydroxyl, halo, —CN, NO₂, is substituted orunsubstituted;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen,C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of which C₁-C₈ alkyl and C₃-C₆cycloalkyl is substituted or unsubstituted;

R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴,—NR⁵R⁶, or —SO₂R⁴, each of which R¹⁰ except hydrogen and halo issubstituted or unsubstituted;

m and q are the same or different and each; and

m′ is 0 or an integer from 1-4.

In an aspect, a compound of formula (Ia-1) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ia-3):

wherein

R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R^(4′) R⁵, and R⁶ issubstituted or unsubstituted;

each R² is the same or different and each is hydrogen, hydroxyl, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, C₁-C₈alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which R² except hydrogen, hydroxyland halo is substituted or unsubstituted;

R³ is hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴,—CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R³except hydroxyl and halo is substituted or unsubstituted;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen,C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of which C₁-C₈ alkyl and C₃-C₆cycloalkyl is substituted or unsubstituted;

R⁴ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴,—NR⁵R⁶, or —SO₂R⁴;

q are the same or different and each; and

m′ is 0 or an integer from 1-4

R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴,—NR⁵R⁶, or —SO₂R⁴, each of which R¹⁰ except hydrogen and halo issubstituted or unsubstituted; and

R^(d) is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,—CN, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴; each of which R^(H) other than hydrogenand —CN is optionally substituted.

In certain embodiments R^(d) is phenyl, thienyl, thiazolyl, furanyl,oxazolyl, pyrazolyl, oxadiazolyl, or imidazolyl, each of which issubstituted or unsubstituted. In certain embodiments R^(d) is phenyl,thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, oxadiazolyl, orimidazolyl, each of which is unsubstituted or substituted with 1 or moresubstituents independently chosen from hydroxyl, cyano, amino,C₁-C₂alkyl, C₁-C₂alkoxy, mono- or di-C₁-C₂alkylamino, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy. In certain embodiments R^(d) is thienyl substitutedwith methyl.

In certain embodiments, the disclosure includes compounds and salts offormula (Ia-3) wherein:

R^(a) is hydrogen, hydroxyl, amino, C₁-C₇alkyl, C₁-C₂alkoxy, and mono-or di-C₁-C₂alkylamino-;

each R² is the same or different and is independently selected fromhydrogen, halo, hydroxyl, —CN, —NO₂, amino, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy;

each R³ is independenty chosen from hydroxyl, halo, —CN, NO₂, C₁-C₂alkyl, C₁-C₂ alkoxy, C₁-C₂haloalkoxy, and C₁-C₂ haloalkyl;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen orC₁-C₂ alkyl;

m′ is 0 or an integer from 1-4; and

R¹⁰ is hydrogen, hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl,C₁-C₄ alkoxy, C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴.

R^(d) in this embodiments can be thienyl substituted with methyl.

In an embodiment of the compound of formula (Ia-2): R^(a) is hydroxyl orsubstituted or unsubstituted —O(C₁-C₈ alkyl); R² is hydrogen,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₁-C₈ alkoxy, or halo; R¹¹ and R¹² are each independently chosen fromsubstituted or unsubstituted C₁-C₈ alkyl (e.g., C₁₄ alkyl, such methyl,ethyl, propyl, or butyl), substituted or unsubstituted C₁-C₈ alkoxy, orhalo (e.g., —F, —I, —Cl, or —Br); R¹⁰ is hydrogen, substituted orunsubstituted C₁-C₈ alkyl, cyclopropyl, —CH₂-cyclopropyl, cyclobutyl,—CH₂-cyclobutyl, —CH═CH₂, —C≡C-cyclopropyl, —C≡C-cyclobutyl, phenyl,benzyl, —I, —CF₃, —NH₂, or —CN; m is 0, 1, or 2; and m′ is 0.

The disclosure also includes a compound or salt of formula (Ia-4):

Within formula (Ia-4):

R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R^(4′) R⁵, and R⁶ issubstituted or unsubstituted;

Each R² is the same or different and is hydrogen, hydroxyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, C₁-C₈ alkoxy,C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl,haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)₄NR⁷C(O)NR⁵R⁶, —(CH₂)₄NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)₄SO₂R⁴,—(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl,each of which R² except hydrogen, hydroxyl and halo is substituted orunsubstituted;

R³ is selected from C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is a 5- or 6-membered heteroaryl having 1, 2, 3, or 4heteroatoms independently chosen from N, O, and S, and where each R³ isunsubstituted or substituted with one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy; each R¹¹ is independently selected from hydroxyl, halo,—CN, NO₂, C₁-C₈ alkyl, C₂-C₅ alkenylC₁-C₈ alkoxy, C₁-C₂ haloalkoxy,C₁-C₂ haloalkyl, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴,—(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶,—(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, and —(CH₂)_(q)SO₂R⁴, each of whichand R¹² other than hydroxyl, halo, —CN, NO₂, is substituted orunsubstituted;

each R⁴, R⁵, R⁶, and R⁷ is the same or different and each is hydrogen,C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of which C₁-C₈ alkyl and C₃-C₆cycloalkyl is substituted or unsubstituted;

R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,halo, C₁-C₈ haloalkyl, aryl, arylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴,each of which R¹⁰ except hydrogen and halo is substituted orunsubstituted;

m is 0 or 1, 2, 3, 4, or 5; and

m′ is 0 or an integer from 1-4.

In an embodiment the disclosure includes a compound or salt of formula(Ia-4) wherein

R^(a) is hydrogen, hydroxyl, amino, C₁-C₂alkyl, C₁-C₂alkoxy, and mono-or di-C₁-C₂alkylamino-;

each R² is the same or different and is independently selected fromhydrogen, halo, hydroxyl, —CN, —NO₂, amino, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy;

R³ is selected from C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is chosen from thienyl, furanyl, thiazolyl, pyrazolyl,imidazolyl; each of which one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy;

Each R¹¹ is independently selected from hydroxyl, halo, —CN, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy;

Each R⁴, R⁵, and R⁶ is the same or different and each is hydrogen orC₁-C₂ alkyl;

m′ is 0 or an integer from 1-4; and

R¹⁰ is hydrogen, hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl,C₁-C₄ alkoxy, C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴.

In certain embodiments, the disclosure includes a compound or salt offormula (Ia-4) in which:

R^(a) is hydrogen, hydroxyl, C₁-C₂alkyl, or C₁-C₂alkoxy;

each R² is the same or different and is independently selected fromhydrogen, halo, hydroxyl, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl,and C₁-C₂haloalkoxy;

R³ is selected from C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is chosen from thienyl, furanyl, thiazolyl, pyrazolyl,imidazolyl; each of which one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy;

Each R¹¹ is independently selected from hydroxyl, halo, —CN, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy;

m′ is 0 or an integer from 1-4; and

R¹⁰ is hydrogen, hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl,C₁-C₄ alkoxy, C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy.

The disclosure further includes compounds and salts of formula (Ia-4) inwhich

R^(a) is hydroxyl; and Each R² is independently chosen from hydrogen andhalogen.

In any of embodiments of formula (Ia-1 to Ia-4) the group

can be a group in which R^(a) is hydroxyl, NHCN, or NHSO₂H, —NHSO₂alkyl,CH₂SO₂phenyl, —NHOH or —NHOalkyl, or can be a group in which —C(O)R^(a)is replaced by —CH₂OH, —P(O)(OH)₂, —P(O)(OH)alkyl, or —SO₂OH.

In some aspects, the compound of formula (Ib) is a compound, prodrug, orpharmaceutically acceptable salt of formula (Ib-1):

wherein

R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R⁴, R⁵, and R⁶ issubstituted or unsubstituted;

R^(b) and R^(e) are the same or different and each is H or substitutedor unsubstituted C₁-C₈ alkyl;

each R² is the same of different and each is hydrogen, hydroxyl, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₁-C₈ alkoxy, C₃-C₆cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl,haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which R² except hydrogen, hydroxyl,halo, —CN, and —NO₂ is substituted or unsubstituted;

R³ is halo, —C(O)R₄, C₂-C₈ alkynyl, haloaryl, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R³ issubstituted or unsubstituted;

each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or different and each ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, each of which C₁-C₈ alkyl, C₂-C₈alkenyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, or heterocycloalkyl issubstituted or unsubstituted;

R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy,C₁-C₈ haloalkyl, halo, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴,—NR⁵R⁶, or —SO₂R⁴, each of which R¹⁰ except hydrogen, hydroxyl, halo,and —CN is substituted or unsubstituted;

X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —O—, —SO—, or —SO₂—, or —S—, each of whichR⁵, R⁸, and

R⁹ is substituted or unsubstituted;

X³ is CH or N; and

m and q are the same or different and each is 0 or an integer from 1-5.

In an embodiment, the compound of formula (Ib-1) comprises R^(a) ishydroxyl or substituted or unsubstituted —O(C₁-C₈ alkyl); R^(b) andR^(e) are each hydrogen; R² is hydrogen; R³ is halo, substituted orunsubstituted —C(O)morpholinyl, or substituted or unsubstituted2-fluorophenyl; R¹⁰ is hydrogen, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted —CH═CH₂, substituted orunsubstituted cyclopropyl, substituted or unsubstituted—C≡C-cyclopropyl, substituted or unsubstituted cyclobutyl, substitutedor unsubstituted cyclobutyl, —OH, —CF₃, —CF₂CF₃, —Cl, —F, —I, —CN,—CH₂CN, —NH₂, substituted or unsubstituted phenyl, substituted orunsubstituted benzyl, or substituted or unsubstituted —CH₂-tetrazolyl; Xis —CH₂— or —NH—; and m is 0, 1, or 2.

Compounds of formula (I), including compounds of formulas (Ia), (Ib),(Ic), and (Id), are set forth below in Table 6 as representativeexamples. Prodrugs and pharmaceutically acceptable salts of theexemplified compounds are also included in the disclosure.

Terminology

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or language denoting examples (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When the substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. When an oxo group substitutes aheteroaromatic moiety, the resulting molecule can sometimes adopttautomeric forms. For example a pyridyl group substituted by oxo at the2- or 4-position can sometimes be written as a pyridine orhydroxypyridine. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates. A stable compound or stable structure ismeant to imply a compound that is sufficiently robust to surviveisolation from a reaction mixture and subsequent formulation into aneffective therapeutic agent. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat aminoalkyl means the point of attachment of this substituent to thecore structure is in the alkyl portion and alkylamino means the point ofattachment is a bond to the nitrogen of the amino group.

Suitable groups that may be present on a “substituted” or “optionallysubstituted” position include, but are not limited to, halogen; cyano;—OH; nitro; alkyl groups (including cycloalkyl and (cycloalkyl)alkylgroups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms;alkenyl and alkynyl groups including groups having one or moreunsaturated linkages and from 2 to about 8, or 2 to about 6 carbonatoms; alkoxy groups having one or more oxygen linkages and from 1 toabout 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy;alkylthio groups including those having one or more thioether linkagesand from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms.For example, suitable groups that may be present on a “substituted” or“optionally substituted” position include hydroxyl, halogen, cyano,alkyl groups, and alkoxy groups.

In any of the embodiments above, the term “alkyl” implies astraight-chain or branched alkyl substituent containing from, forexample, from about 1 to about 8 carbon atoms, e.g., from about 1 toabout 6 carbon atoms. Examples of alkyl group include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, n-hexyl, and the like. This definition also applies wherever“alkyl” occurs as part of a group, such as, e.g., in C₃-C₆cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl,dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino,dialkylamino, arylalkyl, etc. The alkyl can be substituted orunsubstituted, as described herein. Even in instances in which the alkylis an alkylene chain (e.g., —(CH₂)_(n)—), the alkyl group can besubstituted or unsubstituted. An example of a substituted alkylene chainincludes —CF₂-cyclopropyl.

In any of the embodiments above, the term “alkenyl,” as used herein,means a linear alkenyl substituent containing from, for example, about 2to about 8 carbon atoms (branched alkenyls are about 3 to about 8carbons atoms), e.g., from about 3 to about 6 carbon atoms (branchedalkenyls are about 3 to about 6 carbons atoms). In accordance with anembodiment, the alkenyl group is a C₂-C₄ alkenyl. Examples of alkenylgroup include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, and the like. The alkenylcan be substituted or unsubstituted, as described herein.

In any of the embodiments above, the term “alkynyl,” as used herein,means a linear alkynyl substituent containing at least one carbon-carbontriple bond and from, for example, about 2 to about 8 carbon atoms(branched alkynyls are about 4 to about 12 carbons atoms), e.g., fromabout 2 to about 6 carbon atoms (branched alkynyls can be from about 4to about 8 carbon atoms), e.g., from about 2 to about 4 carbon atoms.Examples of such substituents include propynyl, propargyl, n-butynyl,pentynyl, isopentynyl, hexynyl, octynyl, and the like. The alkynyl canbe substituted or unsubstituted, as described herein.

In any of the embodiments above, the term “cycloalkyl,” as used herein,means a cyclic alkyl moiety containing from, for example, 3 to 6 carbonatoms or from 5 to 6 carbon atoms. Examples of such moieties includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Thecycloalkyl can be substituted or unsubstituted, as described herein. Forexample, a substituted cycloalkyl includes a halo- orhaloalkyl-substituted cyclopropyl, such as 2-fluorocyclopropyl,2,2-difluorocyclopropyl, 1-(trifluoromethyl)cyclopropyl, and2-(trifluoromethyl)cyclopropyl.

In any of the embodiments above, the term “hydrocarbyl” means analiphatic group having the specified number of carbon atoms and theappropriate valence in view of the number of substitutions shown in thestructure. Hydrocarbyl groups contain at least carbon and hydrogen, andcan contain single, double, and triple carbon-carbon bonds. In certainembodiments hydrocarbyl groups optionally contain 1 or more (e.g., 1-8)heteroatoms selected from N, O, S, Si, P, or a combination thereof.Hydrocarbyl groups can be unsubstituted or substituted with one or moresubstituent groups up to the valence allowed by the hydrocarbyl group.For example the hydrocarbyl group may be substituted with hydroxyl,cyano, amino, halogen, oxo, cycloalkyl, 5- to 7-memberedheterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, andS, 5- or 6-membered heteroaryl selected with 1 to 5 heteroatoms selectedfrom N, O, and S, and phenyl.

In any of the embodiments above, the term “hydroxy” refers to the group—OH.

In any of the embodiments above, the terms “alkoxy” and “cycloalkyloxy”embrace linear or branched alkyl and cycloalkyl groups, respectively,that are attached to a divalent oxygen. The alkyl and cycloalkyl groupsare the same as described herein. The term “aryloxy” refers tosubstituents that have an aryl group attached to divalent oxygen. Thearyl group is the same as described herein.

In any of the embodiments above, the term “halo” refers to a halogenselected from fluorine, chlorine, bromine, and iodine.

In any of the embodiments above, the term “aryl” refers to a mono, bi,or tricyclic carbocyclic ring system having one, two, or three aromaticrings, for example, phenyl, naphthyl, anthracenyl, or biphenyl. The term“aryl” refers to an unsubstituted or substituted aromatic carbocyclicmoiety, as commonly understood in the art, and includes monocyclic andpolycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl,anthracenyl, pyrenyl, and the like. An aryl moiety generally containsfrom, for example, 6 to 30 carbon atoms, from 6 to 18 carbon atoms, from6 to 14 carbon atoms, or from 6 to 10 carbon atoms. It is understoodthat the term aryl includes carbocyclic moieties that are planar andcomprise 4n+2 π electrons, according to Hückel's Rule, wherein n=1, 2,or 3. This definition also applies wherever “aryl” occurs as part of agroup, such as, e.g., in haloaryl (e.g., monohaloaryl, dihaloaryl, andtrihaloaryl), arylalkyl, etc. The aryl can be substituted orunsubstituted, as described herein.

In any of the embodiments above, the term “heteroaryl” refers toaromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclicgroups, and 11 to 14 membered tricyclic groups which have at least oneheteroatom (O, S, or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicand tricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized, and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring.Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl,pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)-and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl,isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl canbe substituted or unsubstituted, as described herein.

The term “Het” means a “heterocycloalkyl,” which is a stable, monocyclicor bicyclic system containing at least two double bonds, 3 to 7 ringmembers of carbon atoms and one, two, or three heteroatoms selected fromnitrogen, sulfur, and/or oxygen. In an aspect, “Het” is a 5, 6, or7-membered monocyclic ring and contains one, two, or three heteroatomsselected from nitrogen, oxygen, and sulfur. In some instances, “Het” isa heteroaryl, as described herein.

The term “heterocycloalkyl” means a stable, saturated, or partiallyunsaturated monocyclic, bicyclic, and spiro ring system containing 3 to7 ring members of carbon atoms and other atoms selected from nitrogen,sulfur, and/or oxygen. In an aspect, a heterocycloalkyl is a 5, 6, or7-membered monocyclic ring and contains one, two, or three heteroatomsselected from nitrogen, oxygen, and sulfur. The heterocycloalkyl may beattached to the parent structure through a carbon atom or through anyheteroatom of the heterocycloalkyl that results in a stable structure.Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl,imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl,pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl. Theheterocycloalkyl can be substituted or unsubstituted, as describedherein.

In any of the embodiments above, the alkyl, alkoxy, and alkylaminogroups can be linear or branched.

In other aspects, any substituent that is not hydrogen (e.g., C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, or heterocycloalkylalkyl) can be an optionallysubstituted moiety. The substituted moiety typically comprises at leastone substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position(e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.). When an aryl group issubstituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy,and others, the aromatic ring hydrogen is replaced with the substituentand this can take place in any of the available hydrogens, e.g., 2, 3,4, 5, and/or 6-position wherein the 1-position is the point ofattachment of the aryl group in the compound of the present invention.Suitable substituents include, e.g., halo, alkyl, alkenyl, alkynyl,hydroxy, nitro, cyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy,carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido,haloalkylamido, aryl, heteroaryl, and heterocycloalkyl, each of which isdescribed herein. In some instances, the substituent is at least onealkyl, halo, and/or haloalkyl (e.g., 1 or 2).

In any of the embodiments above, whenever a range of the number of atomsin a structure is indicated (e.g., a C₁₋₁₂, C₁₋₈, C₁₋₆, or C₁ alkyl,cycloalkyl, etc.), it is specifically contemplated that any sub-range orindividual number of carbon atoms falling within the indicated rangealso can be used. Thus, for instance, the recitation of a range of 1-8carbon atoms (e.g., C₁-C₈), 1-6 carbon atoms (e.g., C₁-C₆), 1-4 carbonatoms (e.g., C₁-C₄), 1-3 carbon atoms (e.g., C₁-C₃), or 2-8 carbon atoms(e.g., C₂-C₈) as used with respect to any chemical group (e.g., alkyl,cycloalkyl, etc.) referenced herein encompasses and specificallydescribes 1, 2, 3, 4, 5, 6, 7, and/or 8 carbon atoms, as appropriate, aswell as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms,1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms,1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms,2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms,3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms,4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms,etc., as appropriate).

The subscripts “m” and “n” represent the number of substituents, e.g.,R² or R³, in which each substituent, e.g., R² or R³, can be the same ordifferent. The subscripts m and n can be the same or different and eachis either 0 or an integer from 1-5 (i.e., 1, 2, 3, 4, or 5). When m or nis 0, then the corresponding substituent, i.e., R² or R³, is not presentin the compound of formula (I). The subscripts “o” and “q” represent thenumber of methylene repeat units. The subscripts o and q are either 0 oran integer from 1-5 (i.e., 1, 2, 3, 4, or 5). When o or q is 0, then therespective moiety does not contain any methylene repeat units.

In any of the embodiments described herein, a compound of the presentinvention can also be provided as a prodrug, which is a drug derivativeor drug precursor compound that typically is inactive or less than fullyactive until it is converted in the body through a normal metabolicprocess such as, for example, hydrolysis of an ester or amide form ofthe drug, to the active drug. A prodrug may be selected and used insteadof the parent drug because, for example, in its prodrug form it is lesstoxic, and/or may have better absorption, distribution, metabolism andexcretion (ADME) characteristics, and the like, than the parent drug. Aprodrug might also be used to improve how selectively the drug interactswith cells or processes that are not its intended target. This approachmay be employed particularly, for example, to prevent or decreaseadverse effects, especially in cancer treatments, which may beespecially prone to having severe unintended and undesirable sideeffects.

The term “prodrug” denotes a derivative of a compound, which derivative,when administered to warm-blooded animals, e.g., humans, is convertedinto the compound (drug). For example, the enzymatic and/or chemicalhydrolytic cleavage of a derivative compound of the present inventionoccurs in such a manner that the proven drug form is released, and themoiety or moieties split off remain nontoxic or are metabolized so thatnontoxic metabolites are produced. For example, a carboxylic acid groupcan be esterified, e.g., with a methyl group or ethyl group to yield anester. When an ester is administered to a subject, the ester is cleaved,enzymatically or non-enzymatically, reductively, oxidatively, orhydrolytically, to reveal the anionic group. An anionic group can beesterified with moieties (e.g., acyloxymethyl esters) which are cleavedto reveal an intermediate compound which subsequently decomposes toyield the active compound.

The prodrug can be prepared in situ during the isolation andpurification of the compound of formula (I), including a compound offormula (Ia), (Ib), (Ic), or (Id), or by separately reacting thepurified compound with a suitable derivatizing agent. For example,hydroxy groups can be converted into esters via treatment with acarboxylic acid in the presence of a catalyst. Examples of cleavablealcohol prodrug moieties include substituted or unsubstituted, branchedor unbranched alkyl ester moieties, e.g., ethyl esters, alkenyl esters,di-alkylamino alkyl esters, e.g., dimethylaminoethyl ester, acylaminoalkyl esters, acyloxy alkyl esters (e.g., pivaloyloxymethyl ester), arylesters, e.g., phenyl ester, aryl-alkyl esters, e.g., benzyl ester,optionally substituted, e.g., with methyl, halo, or methoxy substituentsaryl and aryl-alkyl esters, amides, alkyl amides, di-alkyl amides, andhydroxy amides.

Knowing the disclosures herein, it will be appreciated also that acompound of the present invention can be in the form of a prodrug, andthat such prodrugs can be prepared using reagents and synthetictransformations that are well-known to those having ordinary skill inthe art. The effectiveness of a particular prodrug can be determinedusing one or more analytical methods (e.g. pharmacokinetics, bioassays,in vivo efficacy studies, and the like) that are well-known to those ofordinary skill in the art.

More specifically, a prodrug of a compound of formula (I), including acompound of formula (Ia), (Ib), (Ic), or (Id), may be prepared usingroutine chemical procedures. For example, a hydroxyl substituent on acompound of formula (I) can be substituted with —CO-alkyl, —CO₂alkyl,—CONH-alkyl, —CO-alkenyl, —CO₂-alkenyl, —CONH— alkenyl, —CO-aryl,—CO₂-aryl, —CONH-aryl, —CO-heterocycle, —CO₂-heterocycle,—CONH-heterocycle, or —PO₃H₂. Specific modifying groups of hydroxylinclude, for example, acetyl, propionyl, isobutyryl, pivaloyl,palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl,dimethylaminomethylcarbonyl, sulfo, alanyl, and fumaryl group.

An amino group can be substituted with —CO-alkyl, —CO₂-alkyl,—CO-alkenyl, —CO₂-alkenyl, —CO₂-aryl, —CO-aryl, —CO-heterocycle,—CO₂-heterocycle, or —PO₃H₂. The alkyl, alkenyl, aryl, and heterocyclemoieties are optionally substituted by halogen, alkyl, hydroxyl, alkoxy,carboxy, amino, an amino acid residue, —PO₃H₂, —SO₃H, —OPO₃H₂, and—OSO₃H. Specific modifying groups of amino include, for example,tert-butyl, docosanoyl, pivaloylmethyloxy, alanyl, hexylcarbamoyl,pentylcarbamoyl, 3-methylthio-1-(acetylamino)propylcarbonyl,1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl, tetrahydrofuranyl, andpyrrolidylmethyl.

Suitable modifying groups of carboxyl include, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pivaloyloxymethyl, carboxymethyl, dimethylaminomethyl,1-(acetyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,1-(isopropyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl,carboxylmethyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, benzyl, phenyl,o-tolyl, morpholinoethyl, N,N-diethylcarbamoylmethyl, and phthalidyl.

In any of the embodiments above, the phrase “salt” or “pharmaceuticallyacceptable salt” is intended to include nontoxic salts synthesized fromthe parent compound which contains a basic or acidic moiety byconventional chemical methods. Generally, such salts can be prepared byreacting the free acid or base forms of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two. For example, an inorganicacid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, orhydrobromic acid), an organic acid (e.g., oxalic acid, malonic acid,citric acid, fumaric acid, lactic acid, malic acid, succinic acid,tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid,ascorbic acid, methylsulfonic acid, or benzylsulfonic acid), aninorganic base (e.g., sodium hydroxide, potassium hydroxide, calciumhydroxide, magnesium hydroxide, or ammonium hydroxide), an organic base(e.g., methylamine, diethylamine, triethylamine, triethanolamine,ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, orcinchonine), or an amino acid (e.g., lysine, arginine, or alanine) canbe used. Generally, non-aqueous media such as ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are typical. Lists of suitablesalts are found in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, p. 1445, and Journal ofPharmaceutical Science, 66, 2-19 (1977). For example, they can be a saltof an alkali metal (e.g., sodium or potassium), alkaline earth metal(e.g., calcium), or ammonium of salt.

The methods described herein comprise administering a compound offormula (I) or a prodrug or a pharmaceutically acceptable salt thereofin the form of a pharmaceutical composition. In particular, apharmaceutical composition will comprise at least one compound offormula (I) or a prodrug or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable excipients described herein, for example, vehicles,adjuvants, carriers or diluents, are well-known to those who are skilledin the art and are readily available to the public. Typically, thepharmaceutically acceptable carrier is one that is chemically inert tothe active compounds and one that has no detrimental side effects ortoxicity under the conditions of use.

The pharmaceutical compositions can be administered as oral, sublingual,transdermal, subcutaneous, topical, absorption through epithelial ormucocutaneous linings, intravenous, intranasal, intraarterial,intramuscular, intratumoral, peritumoral, interperitoneal, intrathecal,rectal, vaginal, or aerosol formulations. In some aspects, thepharmaceutical composition is administered orally or intravenously.

In accordance with any of the embodiments, the compound of formula (I)or a prodrug or a pharmaceutically acceptable salt thereof can beadministered orally to a subject in need thereof. Formulations suitablefor oral administration can consist of (a) liquid solutions, such as aneffective amount of the compound dissolved in diluents, such as water,saline, or orange juice and include an additive, such as cyclodextrin(e.g., α-, β-, or γ-cyclodextrin, hydroxypropyl cyclodextrin) orpolyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets,lozenges, and troches, each containing a predetermined amount of theactive ingredient, as solids or granules; (c) powders; (d) suspensionsin an appropriate liquid; and (e) suitable emulsions and gels. Liquidformulations may include diluents, such as water and alcohols, forexample, ethanol, benzyl alcohol, and the polyethylene alcohols, eitherwith or without the addition of a pharmaceutically acceptablesurfactant, suspending agent, or emulsifying agent. Capsule forms can beof the ordinary hard- or soft-shelled gelatin type containing, forexample, surfactants, lubricants, and inert fillers, such as lactose,sucrose, calcium phosphate, and cornstarch. Tablet forms can include oneor more of lactose, sucrose, mannitol, corn starch, potato starch,alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum,colloidal silicon dioxide, croscarmellose sodium, talc, magnesiumstearate, calcium stearate, zinc stearate, stearic acid, and otherexcipients, colorants, diluents, buffering agents, disintegratingagents, moistening agents, preservatives, flavoring agents, andpharmacologically compatible carriers. Lozenge forms can comprise theactive ingredient in a flavor, usually sucrose and acacia or tragacanth,as well as pastilles comprising the active ingredient in an inert base,such as gelatin and glycerin, or sucrose and acacia, emulsions, gels,and the like containing, in addition to the active ingredient, suchcarriers as are known in the art.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.The compound of formula (I) or a salt thereof can be administered in aphysiologically acceptable diluent in a pharmaceutical carrier, such asa sterile liquid or mixture of liquids, including water, saline, aqueousdextrose and related sugar solutions, an alcohol, such as ethanol,isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol orpolyethylene glycol, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such aspoly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant, such as a soap ora detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils, which can be used in parenteral formulations include petroleum,animal, vegetable, or synthetic oils. Specific examples of oils includepeanut, soybean, sesame, cottonseed, corn, olive, petrolatum, andmineral. Suitable fatty acids for use in parenteral formulations includeoleic acid, stearic acid, and isostearic acid. Ethyl oleate andisopropyl myristate are examples of suitable fatty acid esters. Suitablesoaps for use in parenteral formulations include fatty alkali metal,ammonium, and triethanolamine salts, and suitable detergents include (a)cationic detergents such as, for example, dimethyl dialkyl ammoniumhalides, and alkyl pyridinium halides, (b) anionic detergents such as,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergentssuch as, for example, fatty amine oxides, fatty acid alkanolamides, andpolyoxyethylene-polypropylene copolymers, (d) amphoteric detergents suchas, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazolinequaternary ammonium salts, and (3) mixtures thereof.

The parenteral formulations will typically contain from about 0.5 toabout 25% by weight of the inhibitors in solution. Suitablepreservatives and buffers can be used in such formulations. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain one or more nonionic surfactants having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations ranges from about 5 to about15% by weight. Suitable surfactants include polyethylene sorbitan fattyacid esters, such as sorbitan monooleate and the high molecular weightadducts of ethylene oxide with a hydrophobic base, formed by thecondensation of propylene oxide with propylene glycol. The parenteralformulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, water, for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions can beprepared from sterile powders, granules, and tablets of the kindpreviously described.

The inhibitors may be made into injectable formulations. Therequirements for effective pharmaceutical carriers for injectablecompositions are well known to those of ordinary skill in the art. SeePharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia,Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbookon Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

Topically applied compositions are generally in the form of liquids(e.g., mouthwash), creams, pastes, lotions and gels. Topicaladministration includes application to the oral mucosa, which includesthe oral cavity, oral epithelium, palate, gingival, and the nasalmucosa. In some embodiments, the composition contains at least oneactive component and a suitable vehicle or carrier. It may also containother components, such as an anti-irritant. The carrier can be a liquid,solid or semi-solid. In embodiments, the composition is an aqueoussolution, such as a mouthwash. Alternatively, the composition can be adispersion, emulsion, gel, lotion or cream vehicle for the variouscomponents. In one embodiment, the primary vehicle is water or abiocompatible solvent that is substantially neutral or that has beenrendered substantially neutral. The liquid vehicle can include othermaterials, such as buffers, alcohols, glycerin, and mineral oils withvarious emulsifiers or dispersing agents as known in the art to obtainthe desired pH, consistency and viscosity. It is possible that thecompositions can be produced as solids, such as powders or granules. Thesolids can be applied directly or dissolved in water or a biocompatiblesolvent prior to use to form a solution that is substantially neutral orthat has been rendered substantially neutral and that can then beapplied to the target site. In embodiments of the invention, the vehiclefor topical application to the skin can include water, bufferedsolutions, various alcohols, glycols such as glycerin, lipid materialssuch as fatty acids, mineral oils, phosphoglycerides, collagen, gelatinand silicone based materials.

The compound of formula (I) or a prodrug or a pharmaceuticallyacceptable salt thereof, alone or in combination with other suitablecomponents, can be made into aerosol formulations to be administered viainhalation. These aerosol formulations can be placed into pressurizedacceptable propellants, such as dichlorodifluoromethane, propane,nitrogen, and the like. They also may be formulated as pharmaceuticalsfor non-pressured preparations, such as in a nebulizer or an atomizer.

The dose administered to the mammal, particularly human and othermammals, in accordance with the present invention should be sufficientto affect the desired response. One skilled in the art will recognizethat dosage will depend upon a variety of factors, including the age,condition or disease state, predisposition to disease, genetic defect ordefects, and body weight of the mammal. The size of the dose will alsobe determined by the route, timing and frequency of administration aswell as the existence, nature, and extent of any adverse side-effectsthat might accompany the administration of a particular inhibitor andthe desired effect. It will be appreciated by one of skill in the artthat various conditions or disease states may require prolongedtreatment involving multiple administrations.

The inventive methods comprise administering an effective amount of acompound of formula (I) or a prodrug or a pharmaceutically acceptablesalt thereof. An “effective amount” means an amount sufficient to show ameaningful benefit in an individual, e.g., promoting at least one aspectof tumor cell cytotoxicity (e.g., inhibition of growth, inhibitingsurvival of a cancer cell, reducing proliferation, reducing size and/ormass of a tumor (e.g., solid tumor)), or treatment, healing, prevention,delay of onset, halting, or amelioration of other relevant medicalcondition(s) associated with a particular cancer. The meaningful benefitobserved in the patient can be to any suitable degree (10, 20, 30, 40,50, 60, 70, 80, 90% or more). In some aspects, one or more symptoms ofthe cancer are prevented, reduced, halted, or eliminated subsequent toadministration of a compound of formula (I), including a compound offormula (Ia), (Ib), (Ic), or (Id), or a prodrug or a pharmaceuticallyacceptable salt thereof, thereby effectively treating the cancer to atleast some degree.

Effective amounts may vary depending upon the biological effect desiredin the individual, condition to be treated, and/or the specificcharacteristics of the compound of formula (I)), including a compound offormula (Ia), (Ib), (Ic), or (Id), or a prodrug or a pharmaceuticallyacceptable salt thereof, and the individual. In this respect, anysuitable dose of the compound of formula (I) or a prodrug or apharmaceutically acceptable salt thereof can be administered to thepatient (e.g., human), according to the type of cancer to be treated.Various general considerations taken into account in determining the“effective amount” are known to those of skill in the art and aredescribed, e.g., in Gilman et al., eds., Goodman And Gilman's: ThePharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990;and Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Co.,Easton, Pa., 1990, each of which is herein incorporated by reference.The dose of the compound of formula (I), including a compound of formula(Ia), (Ib), (Ic), or (Id), or a prodrug or a pharmaceutically acceptablesalt thereof desirably comprises about 0.1 mg per kilogram (kg) of thebody weight of the mammal (mg/kg) to about 400 mg/kg (e.g., about 0.75mg/kg, about 5 mg/kg, about 30 mg/kg, about 75 mg/kg, about 100 mg/kg,about 200 mg/kg, or about 300 mg/kg). In another embodiment, the dose ofthe compound of formula (I), including a compound of formula (Ia), (Ib),(Ic), or (Id), comprises about 0.5 mg/kg to about 300 mg/kg (e.g., about0.75 mg/kg, about 5 mg/kg, about 50 mg/kg, about 100 mg/kg, or about 200mg/kg), about 10 mg/kg to about 200 mg/kg (e.g., about 25 mg/kg, about75 mg/kg, or about 150 mg/kg), or about 50 mg/kg to about 100 mg/kg(e.g., about 60 mg/kg, about 70 mg/kg, or about 90 mg/kg).

In an aspect, a compound formula (I) inhibits LDHA and/or LDHB. In anembodiment, a compound of formula (I) is selective for LDHA and/or LDHBrelative to other dehydrogenases (e.g., GAPDH and PHGDH). For example,the compound can be at least 2 times (e.g., at least 5 times, at least10 times, at least 20 times, at least 50 times, or at least 100 times)more selective for LDHA and/or LDHB compared to one or more otherdehydrogenases.

While elevated levels of LDHA are a marker for many types of cancer, themajority of which are glycolytic and/or hypoxic, LDHB can beoverexpressed in some cancers (e.g., lung adenocarcinoma, prostatecancer). See, e.g., McCleland et al., Clin Cancer Res, 2013; 19(4):773-784 and Leiblich et al., Oncogene, 2006; 25(20): 2953-2960. Thus, insome aspects of the invention, it is envisioned to provide a compoundthat can selectively inhibit LDHB or inhibit both LDHA and LDHA. In anembodiment, a compound of formula (I) can effectively inhibit LDHB. Insuch embodiments, the compound may or may not have selectivity for LDHA,such that the inhibition is more selective for LDHA compared to LDHB orthe inhibition of LDHA is about equal to the inhibition of LDHB or theinhibition is more selective for LDHB relative to LDHA.

Inhibition of LDHA and/or LDHB has been described in the art as a viabletreatment of cancer. See, e.g., Billiard et al. (Cancer and Metabolism,2013, 1(19): 1-17). Thus, certain invention compounds of formula (I),which includes compounds of formulas (Ia), (Ib), (Ic), and (Id), or aprodrug or pharmaceutically acceptable salt thereof, can be administeredto a patient in need thereof to treat cancer. While not wishing to bebound by any particular theory, it is believed that inhibition of LDHstimulates mitrochondrial respiration and reduces cellular proliferativeand tumorigenic potential. Anti-cancer activity can be measured by anysuitable method, including the assays described herein. In general,activity will be measured as a function of lactate output, % ECAR(extracellular acidification rate), which quantifies glycolysis, and/or% OCR (oxygen consumption rate), which is a measure of mitochondrialrespiration.

The type of cancer is not particularly limited, but in certain aspects,the cancer is characterized as hypoxic and/or highly glycolytic relativeto normal tissue of the same type. “Hypoxic” cells as used hereinrelates to one or more cells that are exposed, transiently orpermanently, to an oxygen partial pressure (pO2) that is lower than thetypical pO2 in cells in tissue that is considered as normal or healthy.Hypoxic cells can include, for example, cells with reduced or no accessto vasculature, such as in a solid tumor.

Examples of cancer treatable with the inventive method include cancersof the head and neck, eye, skin, mouth, throat, esophagus, chest, bone,lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries,kidney, liver, pancreas, brain, intestine, heart, or adrenals. Moreparticularly, cancers include solid tumor, sarcoma, carcinomas,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma,melanoma, neuroblastoma, retinoblastoma, a blood-borne tumor, acutelymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acutelymphoblastic T-cell leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acutenonlymphocyctic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia, hairy cell leukemia, or multiple myeloma. See,e.g., Harrison's Principles of Internal Medicine, Eugene Braunwald etal., eds., pp. 491 762 (15th ed. 2001). In some aspects, the cancer is asolid tumor. In accordance with an embodiment, the cancer is selectedfrom leukemia, melanoma, liver cancer, pancreatic cancer, lung cancer,colon cancer, brain cancer, ovarian cancer, breast cancer, prostatecancer, and renal cancer. In another embodiment, the cancer is livercancer, pancreatic cancer, non-small cell lung cancer, breast cancer, orrenal cancer.

The invention provides a method of treating a patient with cancer cellsresistant to an anti-cancer agent, comprising administering to thepatient an effective amount of the compound of formula (I), including acompound of formula (Ia), (Ib), (Ic), or (Id), or a prodrug or apharmaceutically acceptable salt thereof, and the anti-cancer agent,whereby the compound, prodrug, or pharmaceutically acceptable saltthereof re-sensitizes the cancer cells to the anti-cancer agent. Thecancer cell is the same as described herein. In accordance with anembodiment, the cancer cells are selected from leukemia, melanoma, livercancer, pancreatic cancer, lung cancer, colon cancer, brain cancer,ovarian cancer, breast cancer, prostate cancer, and renal cancer. Inanother embodiment, the cancer cells are liver cancer, pancreaticcancer, non-small cell lung cancer, breast cancer, or renal cancer.

In certain embodiments of this method, the compound of formula (I),including a compound of formula (Ia), (Ib), (Ic), or (Id), or a prodrugor a pharmaceutically acceptable salt thereof can be co-administeredwith an anti-cancer agent (e.g., a chemotherapeutic agent) and/orradiation therapy. In an aspect, the method comprises administering anamount of a compound, prodrug, or salt that is effective to sensitizethe cancer cells to one or more therapeutic regimens (e.g., chemotherapyor radiation therapy). The terms “co-administered” or“co-administration” refer to simultaneous or sequential administration.A compound may be administered before, concurrently with, or afteradministration of another compound.

One or more than one, e.g., two, three, or more anti-cancer agents canbe administered. In this regard, the present invention is directed apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a combination of the compound of formula (I), including acompound of formula (Ia), (Ib), (Ic), or (Id), or a prodrug or apharmaceutically acceptable salt thereof and at least one anti-canceragent (e.g., chemotherapeutic agent).

Examples of anti-cancer agents include platinum compounds (e.g.,cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa,melphalan, busulfan, procarbazine, streptozocin, temozolomide,dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin,doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycinC, plicamycin, dactinomycin), taxanes (e.g., paclitaxel and docetaxel),antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed,thioguanine, floxuridine, capecitabine, and methotrexate), nucleosideanalogues (e.g., fludarabine, clofarabine, cladribine, pentostatin,nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan),hypomethylating agents (e.g., azacitidine and decitabine), proteosomeinhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide andteniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vincaalkaloids (e.g., vicristine, vindesine, vinorelbine, and vinblastine),tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib,sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab,cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab,gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine,fotemustine, and lomustine), enzymes (e.g., L-Asparaginase), biologicalagents (e.g., interferons and interleukins), hexamethylmelamine,mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide),steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonalagents (e.g., tamoxifen, raloxifene, leuprolide, bicaluatmide,granisetron, flutamide), aromatase inhibitors (e.g., letrozole andanastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenaseinhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates,aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac,tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2(COX-2) inhibitors, or any combination thereof.

For purposes of the present invention, the term “patient” typically isdirected to a mammal. For example, the subject can be any patient with adisease that requires chemotherapy and/or radiation therapy. Mammalsinclude, but are not limited to, the order Rodentia, such as mice, andthe order Logomorpha, such as rabbits. In some aspects, the mammals arefrom the order Carnivora, including Felines (cats) and Canines (dogs),Artiodactyla, including Bovines (cows) and Swines (pigs) or of the orderPerssodactyla, including Equines (horses). In some aspects, the mammalsare of the order Primates, Ceboids, or Simioids (monkeys) or of theorder Anthropoids (humans and apes). In embodiments of the invention,the patient is a human.

The invention is further directed to a method of inhibiting lactatedehydrogenase A (LDHA) and/or lactate dehydrogenase b (LDHB) activity ina cell comprising administering a compound of formula (I), including acompound of formula (Ia), (Ib), (Ic), or (Id), or a prodrug or apharmaceutically acceptable salt thereof to a cell, whereby activity ofLDHA and/or LDHB is inhibited. LDHA and LDHB activity can be measured byany method known in the art for measuring enzyme inhibtions, includingby the assays described herein. Typically, inhibition of LDHA and LDHBactivity will be demonstrated by a decrease in lactate accumulationand/or an increase in pyruvate relative to a control sample.

The following examples are provided for further illustration, and shouldnot be construed as limiting in any way.

EXAMPLES Example 1

This example describes a human LDHA primary biochemical assay employedin the characterization of a compound of formula (I) in an embodiment ofthe invention.

Test compounds were placed in a Greiner Bio-One (Monroe, N.C.) 1536-wellblack solid bottom assay plate. 200 millimolar (mM) Tris HCl, pH 7.4,100 micromolar (μM) EDTA and 0.01% TWEEN-20™, final concentration, wasused as the assay buffer. The LDHA reagent was 2 nanomolar (nM) HumanLDHA (Meridian Life Science, Inc., Memphis, Tenn.), final concentration,in assay buffer. The substrate reagent was 0.06 mM NADH and 0.2 mMsodium pyruvate, final concentration, in assay buffer. Theresazurin/diaphorase coupling reagent was 0.037 mM resazurin and 0.133milligrams per milliliter (mg/mL) diaphorase, final concentration, inassay buffer. The sequence of steps, amount and types of reagents, andtime required for each step are set forth in Table 1. The inhibition ofLDHA activity was measured by fluorescence emission.

TABLE 1 Sequence Parameter Value Notes 1 Reagent 3 μL LDHA reagent 2Compound 23 nL Compound of formula (I) 3 Time 15 min RT incubation 4Reagent 1 μL Substrate reagent 5 Time 7 min RT incubation 6 Reagent 1 μLResazurin/diaphorase coupling reagent 7 Detector Fluorescence VIEWLUX ™in end-point (ex 525 nm/ mode: 2 sec exp., 5000 em 598 nm) excitationenergy

Example 2

This example describes a human LDHB counterscreen biochemical assayemployed in the characterization of a compound of formula (I) in anembodiment of the invention.

Test compounds were placed in a Greiner Bio-One (Monroe, N.C.) 1536-wellblack solid bottom assay plate. 200 mM Tris HCl, pH 7.4, 100 μM EDTA and0.01% TWEEN-20™, final concentration, was used as the assay buffer. TheLDHB reagent was 2 nM Human LDHB (Meridian Life Science, Inc., Memphis,Tenn.), final concentration, in assay buffer. The substrate reagent was0.13 mM NADH and 0.16 mM sodium pyruvate, final concentration, in assaybuffer. The resazurin/diaphorase coupling reagent was 0.037 mM resazurinand 0.133 mg/mL diaphorase, final concentration, in assay buffer. Thesequence of steps, amount and types of reagents, and time required foreach step are set forth in Table 2. The inhibition of LDHB activity wasmeasured by fluorescence emission.

TABLE 2 Sequence Parameter Value Notes 1 Reagent 3 μL LDHB reagent 2Compound 23 nL Compound of formula (I) 3 Time 15 min RT incubation 4Reagent 1 μL Substrate reagent 5 Time 7 min RT incubation 6 Reagent 1 μLResazurin/diaphorase coupling reagent 7 Detector Fluorescence VIEWLUX ™in end-point (ex 525 nm/ mode: 2 sec exp., 5000 em 598 nm) excitationenergy

Example 3

This example describes a human PHGDH counterscreen biochemical assayemployed in the characterization of a compound of formula (I) in anembodiment of the invention.

Test compounds were placed in a Greiner Bio-One (Monroe, N.C.) 1536-wellblack solid bottom assay plate. 50 mM TEA, pH 8.0, 10 mM MgCl₂, 0.05%BSA, and 0.01% TWEEN-20™, final concentration, was used as the assaybuffer. The substrate reagent was 10 μM EDTA, 0.625 mM glutamate, 500 nMhuman PSAT1, 500 nM human PSPH, 0.05 mM 3-phosphoglycerate, 0.1 mMresazurin, and 0.1 mg/mL diaphorase, final concentration, in assaybuffer. The PHGDH reagent was 0.15 mM NAD⁺ and 10 nM human PHGDH, finalconcentration, in assay buffer. The sequence of steps, amount and typesof reagents, and time required for each step are set forth in Table 3.The inhibition of PHGDH activity was measured by fluorescence emission.

TABLE 3 Sequence Parameter Value Notes 1 Reagent 3 μL Substrate reagent2 Compound 23 nL Compound of formula (I) 3 Reagent 1 μL PHGDH reagent 4Detector Fluorescence VIEWLUX ™ in end-point (ex 525 nm/ mode: 2 secexp., 5000 em 598 nm) excitation energy, use Δ between 0 and 30 min

Example 4

This example describes a human GAPDH counterscreen biochemical assayemployed in the characterization of a compound of formula (I) in anembodiment of the invention.

Test compounds were placed in a Greiner Bio-One (Monroe, N.C.) 1536-wellblack solid bottom assay plate. 105 mM Tris HCl, pH 7.4, 1004 EDTA, 1.27mM KH₂PO₄, 0.875 mM MgCl₂, 0.0875% BSA, 0.01 mM DTT, and 0.01%TWEEN-20™, final concentration, was used as the assay buffer. Thesubstrate reagent was 0.48 mM glyceraldehyde 3-phosphate, 0.06 mMresazurin, and 0.21 mg/mL diaphorase, final concentration, in assaybuffer. The GAPDH reagent was 0.007 mM NAD⁺ and 2.5 nM human GAPDH,final concentration, in assay buffer. The sequence of steps, amount andtypes of reagents, and time required for each step are set forth inTable 4. The inhibition of GAPDH activity was measured by fluorescenceemission.

TABLE 4 Sequence Parameter Value Notes 1 Reagent 3 μL Substrate reagent2 Compound 23 nL Compound of formula (I) 3 Reagent 1 μL GAPDH reagent 4Detector Fluorescence VIEWLUX ™ in kinetic (ex 525 nm/ mode: 1 sec exp.,5000 em 598 nm) excitation energy, use Δ between 0 and 20 min

Example 5

This example describes cell-based metabolite assay by mass spectrometry(MS) employed in the characterization of a compound of formula (I) in anembodiment of the invention.

The sequence of steps, amount and types of reagents, and time requiredfor each step are set forth in Table 5.

TABLE 5 Sequence Parameter Value Notes 1 Reagent Snu398 cells 100 k/wellin 100 μL RPMI 10% FBS - phenol red 2 Time 24 h 37° C., 5% CO₂incubation 3 Reagent Wash Aspirate media and replace with fresh 4Reagent Compound Dose LDHA inhibitors/controls in media 5 Time 48 h 37°C., 5% CO₂ incubation 6 Reagent Media Aspirate 75 μL of media andcollect in separate plate. Snap freeze and store at −80° C.Pyruvate/lactate/NADH ion counts collected by Quintara Discovery, Inc.using MS-MS.

Example 6

This example describes a cell-based metabolite assay bycolorimetric/fluorometric detection employed in the characterization ofa compound of formula (I) in an embodiment of the invention.

Cell-based HT Lactate assay is a miniaturized Biovision LactateColorimetric/Fluorometric Assay Kit (Cat# K607-100). The assay isroughly a 3.5 hour assay run in a 1536 plate format. Cell numberoptimization should be run for each cell line to achieve an optimalnumber in which lactate production equals roughly 90% of the standardcurve range. Cell number per well optimization has been performed withthe following cell lines: MiaPaCa2—500 cells/well, SNU398—500cells/well, and P493—500 cells/well. The sequence of steps, amount andtypes of reagents, and time required for each step are set forth inTable 6.

TABLE 6 Sequence Parameter Value Notes 1 Reagent MiaPaCa2 500/well in 4μL in DMEM cells 4.5 g/L Glucose, - Glutamate, - FBS, - Phenol Red 2Reagent Compound Dose LDHA inhibitors with pin tool 3 Time 2.5 hr 37°C., 5% CO2 incubation 4 Reagent Compound 2 μL/well 5 Time 48 h RT 6 ReadMedia Absorbance (570 nm) and Fluorescence (Ex/Em = 535/590 nm)

Example 7

This example describes the preparation of tert-butyl2-bromothiazole-4-carboxylate 1 in an embodiment of the invention.

Tert-butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mmol, 2 eq) wasadded to a stirred suspension of 2-bromothiazole-4-carboxylic acid (10g, 48.1 mmol, 1 eq) in dichloromethane (DCM) (100 mL) andtetrahydrofuran (THF) (50 mL), followed by dropwise addition of BF₃.OEt₂(0.938 ml, 7.40 mmol, 10 mol %). The mixture was stirred at roomtemperature for 16 h, concentrated, quenched slowly with a saturatedbicarbonate solution, and extracted with ethyl acetate. The organiclayer was washed with saturated bicarbonate and brine, then dried, andthe crude product was purified in a Biotage (Charlotte, N.C.) flashsystem eluting with 5-30% ethyl acetate in hexanes over 12 columnvolumes. The product fraction was concentrated to provide tert-butyl2-bromothiazole-4-carboxylate 1 as a white solid (10.4 g, 82%).

Example 8

This example describes the preparation of tert-butyl2-hydrazinylthiazole-4-carboxylate 2 in an embodiment of the invention.See Scheme 1.

A solution of tert-butyl 2-bromothiazole-4-carboxylate 1 (10.96 g, 41.5mmol, 1 eq) from Example 1 and hydrazine hydrate (13 ml, 415 mmol, 10eq) in EtOH (80 mL) was refluxed for 2 hr. After completion of thereaction, the solvent was removed and ice water was added. Theprecipitate formed was collected by filtration, washed with cold water,and dried under air. The crude product (tert-butyl2-hydrazinylthiazole-4-carboxylate 2) was pure enough to be used for thefollowing reaction.

Example 9

This example describes the preparation of ethyl2-hydrazinylthiazole-4-carboxylate 3 in an embodiment of the invention.See Scheme 1.

Ethyl bromopyruvate (15.71 ml, 113 mmol) was added to a suspension of2-acetylhydrazinecarbothioamide (15 g, 113 mmol) in ethanol (200 mL) andstirred at room temperature for 30 minutes until the solution becameclear, then refluxed for 1.5 h. The solution was then concentrated andagitated with 20 mL of MeOH and 300 mL of ether. The yellow precipitatewas collected by filtration, washed with ether, and dried to obtain ayellow solid (ethyl 2-hydrazinylthiazole-4-carboxylate 3) as HBr salt.

Example 10

This example describes a general procedure for the synthesis ofsubstituted benzoyl acetonitriles 4 in an embodiment of the invention.

Acetonitrile (ACN) (5.33 ml, 102 mmol, 2 eq) was added dropwise to acooled solution of 1 molar lithium diisopropylamide (LDA) (102 ml, 102mmol, 2 eq) in THF (40 mL) at −78° C. The reaction mixture was stirredfor 30 minutes, and then a solution of an acid chloride (51.0 mmol, 1eq) in 20 mL of THF was added dropwise over 15 minutes. The reaction wasallowed to come to room temperature over 4 h and then quenched with 1 M(molar) HCl. The product was extracted ethyl acetate. The organic layerwas subsequently washed with water and brine and dried over MgSO₄. Thecrude product was purified on Biotage (Charlotte, N.C.) flash systemeluting with 5-75% ethyl acetate in hexanes over 12 column volumes toobtain a substituted benzoyl acetonitrile 4 as a yellow solid.

Example 11

This example describes a general procedure for the synthesis of4-(2-cyano-3-oxo-3-arylpropyl)benzenesulfonamide 5 in an embodiment ofthe invention. See Scheme 2.

2,6-Dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester(Hantzsch ester) (12.21 g, 48.2 mmol, 1.4 eq) and L-proline (0.793 g,6.89 mmol, 20 mol %) were added to a solution of3-oxo-3-phenyl-propanenitrile 4 (34.4 mmol, 1 eq) and4-formylbenzenesulfonamide (7.02 g, 37.9 mmol, 1.1 eq) in ethanol (150mL). The mixture was stirred at 60° C. for 30 minutes. The mixture wasthen cooled, mixed with silica gel, concentrated, and purified on aBiotage (Charlotte, N.C.) flash system with 20-100% ethyl acetate inhexanes over 6 column volumes then with 100% ethyl acetate over 8 columnvolumes to obtain 4-(2-cyano-3-oxo-3-arylpropyl)benzenesulfonamide 5 asa white solid.

Example 12

This example describes a general procedure for the synthesis of2-(5-amino-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate6 in an embodiment of the invention. See Scheme 2.

A mixture of ethyl 2-hydrazinylthiazole-4-carboxylate hydrogen bromidesalt (3, 1.5 g, 5.59 mmol, 1 eq),4-(2-cyano-3-oxo-3-arylpropyl)benzenesulfonamide (5.59 mmol, 1 eq) andtosic acid (2.128 g, 11.19 mmol, 2 eq) in ethanol (15 mL) was heated ina microwave for 15 minutes. The precipitate formed was collected byfiltration and washed with cold ethanol to obtain pure product (ethyl2-(5-amino-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate6) as a yellow solid.

Example 13

This example describes a general procedure for the synthesis of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 in an embodiment of the invention. See Scheme 2.

Tosic acid (5.37 g, 28.2 mmol, 3.5 eq) was added to a suspension ofethyl2-(5-amino-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate6 (8.07 mmol, 1 eq) in ACN (100 mL) and stirred for 10 minutes. Duringthis period, the solution became clear, then a premixed solution ofNaNO₂ (1.113 g, 16.13 mmol, 2 eq) and KI (4.02 g, 24.20 mmol, 3 eq) in10 mL water was added dropwise over a period of 10-15 minutes at roomtemperature. The reaction mixture was allowed to stir at roomtemperature overnight. After completion of the reaction, the excesssolvent was removed under reduce pressure, and the crude product wasextracted with ethyl acetate. The organic layer was subsequently washedwith saturated sodium thiosulfate solution, water, and brine. The crudeproduct was purified on a Biotage (Charlotte, N.C.) flash system using ahigh performance column eluting with either 1-15% acetone indichloromethane or 1-100% ethyl acetate in hexanes over 20 columnvolumes to obtain pure products.

Example 14

This example describes a general procedure for the trifluoromethylationof ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates7 in an embodiment of the invention.

A mixture of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 (0.4 g, 0.673 mmol) 7 and1,10-phenanthroline)(trifluoromethyl)copper(I) 8 (0.316 g, 1.009 mmol,1.5 eq) was degassed with argon, then DMF (2 mL) was added and stirredat 55° C. for 1 h. The reaction mixture was diluted with ethyl acetateand washed with 1 molar HCl, water, and brine. The organic layer wasdried with MgSO₄, concentrated, and purified on a Biotage (Charlotte,N.C.) flash system eluting with 20-100% ethyl acetate in hexanes over 12column volumes to obtain an ethyl2-(5-trifluoromethyl-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate9 as a white solid.

Example 15

This example describes a general procedure for the Suzuki coupling ofethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates7 in an embodiment of the invention. See Scheme 3.

In a sealed microwave vial, 2 molar Na₂CO₃ (0.17 mL, 0.336 mmol, 2 eq)was added to a mixture of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 (0.168 mmol, 1 eq), SILIACAT™ DPP-Pd (0.1 g), boronic acid (0.336mmol, 2 eq) in dimethyl ether (DME) (2 mL), then heated in a microwavefor 30 minutes at 130° C. The reaction mixture was concentrated byblowing forced air. The residue was taken up in DMF (2 mL) and stirredwith a silica-bound DMT, followed by filtering through a thiol resincartridge to remove any leached palladium. Finally the compounds werepurified on a preparative HPLC to obtain pure coupling products 10.

Example 16

This example describes a general procedure for the Sonogashira couplingof ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates(7) in an embodiment of the invention. See Scheme 3.

A mixture of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 (0.202 mmol, 1 eq), bis(triphenylphosphine)palladium(II) chloride(0.014 g, 0.020 mmol, 10 mol %), and CuI (3.84 mg, 0.020 mmol, 10 mol %)in THF (1 mL) was added triethylamine (TEA) (0.169 ml, 1.211 mmol, 6 eq)followed by the alkyne (0.404 mmol, 2 eq) under a nitrogen atmosphere.The vial was sealed and stirred at 80° C. for 4 h. After completion ofthe reaction, the product was extracted with ethyl acetate and theorganic layer was washed with 1 molar HCl and brine. The crude productwas purified on a Biotage (Charlotte, N.C.) flash system eluting with20-100% ethyl acetate or in preparative HPLC to obtain pure couplingproducts 10.

Example 17

This example describes a general procedure for the cyanation of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates7 in an embodiment of the invention. See Scheme 3.

A mixture of ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 (0.168 mmol, 1 eq) and CuCN (0.023 g, 0.252 mmol, 1.5 eq) indimethylsulfoxide (DMSO) (0.5 ml) was heated in a microwave for 0.5 h at160° C. The product was extracted with ethyl acetate. The organic layerwas washed with a saturated bicarbonate solution, water, and brine. Thecrude product was purified on a Biotage (Charlotte, N.C.) flash systemeluting with 30-100% ethyl acetate in hexanes over 15 column volumes toobtain pure products 10.

Example 18

This example describes a general procedure for the hydrolysis of theethyl and methyl esters 10 in an embodiment of the invention. See Scheme3.

A 1.5 molar solution of LiOH in water was added to a solution of ethyl2-(3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate10 (0.252 mmol, 1 eq) in THF/MeOH (3 mL/1.5 mL) and stirred at roomtemperature for 0.5-1 h. After completion of the reaction, the solventwas evaporated under reduced pressure, and the residue was taken up inDMSO. Finally the compounds 11 were purified on preparative HPLC.

Example 19

This example describes a general procedure for the ethyl2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate12a in an embodiment of the invention (Scheme 4, Step a).

DMSO (2.5 mL) was added to a solution of KF (0.147 g, 2.52 mmol, 3 eq)in 0.9 mL water, followed by ethyl2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate7 (0.841 mmol, 1 eq), PdCl₂(dppf)-CH₂Cl₂ adduct (0.137 g, 0.168 mmol, 20mol %), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(0.246 g, 1.262 mmol, 1.5 eq). The mixture was bubbled with argon for 2minutes. Next, the vial was sealed and stirred on a preheated heatingblock at 130° C. for 3 h, then another portion of 0.9 mL of water wasadded, and the mixture was stirred at 130° C. for another 21 h. Aftercompletion of the reaction, a silica-bound metal scavenger was added andstirred for 30 minutes. The reaction mixture was diluted with ethylacetate and filtered through a silica plug. The filtrate was washed withwater, saturated ammonium chloride, and brine. The crude product waspurified on a Biotage (Charlotte, N.C.) flash system eluting with20-100% ethyl acetate in hexanes to obtain pure product ethyl2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate12a as a white solid.

Example 20

This example describes a general procedure for the2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 12b in an embodiment of the invention. See Scheme 4, Step c.

A mixture of ethyl2-(5-(cyanomethyl)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate12a (0.049 mmol) and hydroxytrimethylstannane (0.018 g, 0.099 mmol, 2eq) in dichloroethane (DCE) was stirred at 80° C. for 24 h. The solventwas removed by forced air. The residue was taken up DMSO and passedthrough a sulfonic acid cartridge to remove the trimethyl tin hydroxide.The crude product2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 12b was purified on HPLC.

Example 21

This example describes a general procedure for the synthesis oftetrazoles 13a in an embodiment of the invention. See Scheme 4, Step b.

A mixture of ethyl2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate12a (0.414 mmol, 1 eq), NH₄Cl (0.066 g, 1.241 mmol, 3 eq), and NaN₃(0.081 g, 1.241 mmol, 3 eq) in DMF (2 ml) was heated in a microwave for2 h at 125° C. The product was purified on a reverse phase flash systemto obtain pure products 13a.

Example 22

This example describes a general procedure for the synthesis oftetrazole derivatives 13c in an embodiment of the invention. See Scheme4, Step e.

A solution of ethyl2-(5-((1H-tetrazol-5-yl)methyl)-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate13a (0.091 mmol, 1 eq) in THF (3 ml) was added LiAlH₄ (0.363 ml, 0.363mmol, 4 eq) upon cooling. The reaction mixture was stirred at roomtemperature for 1 and then quenched with water. The residue wassuspended in a DCM/MeOH mixture and filtered through a silica plug. Thecrude product 13c obtained after evaporating the solvent was purified ona preparative HPLC.

Example 23

This example describes the preparation ofN,N-bis(3,4-dimethoxybenzyl)-4-nitrobenzenesulfonamide 14 in anembodiment of the invention. See Scheme 5, first step.

4-Nitrobenzene-1-sulfonyl chloride (1.746 g, 7.88 mmol, 1 eq) was addedto a solution of bis(3,4-dimethoxybenzyl)amine (2.5 g, 7.88 mmol, 1 eq)and Hünig's base (2.75 ml, 15.75 mmol, 2 eq) in DCM (15 ml) uponcooling. The reaction mixture was stirred at room temperature for 1 h.The crude product obtained after evaporating the solvent was purified ona Biotage (Charlotte, N.C.) flash system eluting with 25-100% ethylacetate in hexanes to obtainN,N-bis(3,4-dimethoxybenzyl)-4-nitrobenzenesulfonamide 14 as a yellowsolid. Yield (2.85 g, 72%).

Example 24

This example describes the preparation of4-amino-N,N-bis(3,4-dimethoxybenzyl)benzenesulfonamide 15 in anembodiment of the invention. See Scheme 5, second step.

A solution of ammonium chloride (0.8 g, 14.92 mmol) in 10 mL water andiron powder (1.389 g, 24.87 mmol) was added to a suspension ofN,N-bis(3,4-dimethoxybenzyl)-4-nitrobenzenesulfonamide 14 (2.5 g, 4.97mmol, 1 eq) in ethanol (50 mL). The reaction mixture was stirredovernight at 85° C. The reaction mixture was diluted with methanol andfiltered through a pad of CELITE™. The filtrate was concentrated,neutralized with bicarbonate, and extracted with DCM. The DCM layer waswashed with bicarbonate and brine. The crude product was purified on aBiotage (Charlotte, N.C.) flash system eluting with 1-15% MeOH(ammoniated) in DCM to obtain4-amino-N,N-bis(3,4-dimethoxybenzyl)benzenesulfonamide 15 as a whitesolid. Yield (2.2 g, 94%).

Example 25

This example describes a general preparation ofN,N-bis(3,4-dimethoxybenzyl)-4-((3-aryl-1H-pyrazol-4-yl)amino)-benzenesulfonamide16 in an embodiment of the invention. See Scheme 5, third step.

A mixture of 4-bromo-3-aryl-1H-pyrazole (1.569 mmol, 1 eq),4-amino-N,N-bis(3,4-dimethoxybenzyl)benzenesulfonamide 15 (1.038 g,2.197 mmol, 1.4 eq), t-butyl BrettPhos (CAS #1160861-53-9) (StemChemicals, Newburyport, Mass., Catalog #15-1164) (0.038 g, 0.078 mmol, 5mol %) and t-butyl BrettPhos Palladacycle (CAS #1148148-01-9) (StemChemicals, Newburyport, Mass., Catalog #46-0325) (0.067 g, 0.078 mmol, 5mol %) in a microwave (MW) vial was purged with argon, and then THF (4ml) was added, followed by lithium hexamethyldisilazide (LHMDS) (2.62ml, 3.92 mmol, 2.5 eq). The mixture was stirred in a preheated block at80° C. for 14 h. The reaction mixture was poured into acidified water (1molar HCl) and extracted with ethyl acetate. The organic layer waswashed with water and brine. The crude productN,N-bis(3,4-dimethoxybenzyl)-4-((3-aryl-1H-pyrazol-4-yl)amino)-benzenesulfonamide16 was purified on a Biotage (Charlotte, N.C.) flash system eluting with30-100% ethyl acetate in hexanes.

Example 26

This example describes a general preparation of tert-butyl2-(4-((4-(N,N-bis(3,4-dimethoxybenzyl)sulfamoyl)phenyl)-amino)-3-aryl-1H-pyrazol-1-yl)thiazole-4-carboxylate17 in an embodiment of the invention. See Scheme 5, fourth step.

A mixture ofN,N-bis(3,4-dimethoxybenzyl)-4-((3-aryl-1H-pyrazol-4-yl)amino)benzenesulfon-amide16 (0.732 mmol, 1 eq), K₂CO₃ (0.202 g, 1.464 mmol), and tert-butyl2-bromothiazole-4-carboxylate (0.213 g, 0.805 mmol, 1.1 eq) in DMSO (1.5mL) was stirred for 12 h at 125° C. The reaction mixture was dilutedwith ethyl acetate and filtered through a pad of CELITE™. The filtratewas washed with saturated ammonium chloride and brine. The crude producttert-butyl2-(4-((4-(N,N-bis(3,4-dimethoxybenzyl)sulfamoyl)phenyl)-amino)-3-aryl-1H-pyrazol-1-yl)thiazole-4-carboxylate17 was purified on a Biotage (Charlotte, N.C.) flash system eluting with40-100% ethyl acetate in hexanes.

Example 27

This example describes a general procedure for the deprotection of(N,N-bis(3,4-dimethoxybenzyl) and t-butyl groups and synthesis ofcompounds 18 in an embodiment of the invention. See Scheme 5, fifthstep.

Tert-butyl2-(4-((4-(N,N-bis(3,4-dimethoxybenzyl)sulfamoyl)-phenyl)amino)-3-aryl-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.251 mmol) 17 in a mixture of DCM (1.5 mL) and trifluoroacetic acid(TFA) (1.5 mL) was heated in microwave at 100° C. for 15 min at normalabsorption. The solvent was removed by forced air, the crude product 18was dissolved in DMSO, and then purified using preparative HPLC.

Example 28

This example describes the synthesis of2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 19 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(4-bromo-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (1058mg, 4.48 mmol), 3-bromo-4-phenyl-1H-pyrrole (995 mg, 4.48 mmol), andK₂CO₃ (929 mg, 6.72 mmol). The tube was sealed and DMSO (4 ml) wasadded. The mixture was heated at 120° C. for 4 h. The mixture was pouredinto vigorously stirred H₂O (100 mL), and the solid was filtered,triturated with H₂O, and dried. The solid was re-dissolved in EtOAc andfiltered. Some undissolved material was the hydrolized acid. Thefiltrate was concentrated and triturated with ca. 3% EtOAc/hexane togive ethyl 2-(4-bromo-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(1329 mg, 3.51 mmol, 78% yield).

Step 2: Synthesis of Ethyl2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(4-bromo-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (378 mg, 1mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (330mg, 1.300 mmol), PdCl₂(dppf) (73.2 mg, 0.100 mmol), and potassiumacetate (294 mg, 3.00 mmol). The tube was sealed and air was removed andre-filled with N₂ (2-3 times). Then, 1,4-dioxane (4 ml) was added andstirred at 95° C. (pre-heated) for overnight. The mixture was dilutedwith EtOAc and filtered through CELITE™ and eluted with EtOAc. Afterremoval of the solvent, the product was purified by silica gelchromatography using 10-25% EtOAc/hexane as the eluent to give product,which was triturated with a small amount of hexane and then dried togive ethyl2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(540 mg, 0.762 mmol, 76% yield) as solid. The product contained about40% of reduction (de-Br) product, which was used for the next stepwithout further purification.

Step 3: Synthesis of Ethyl2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(70.9 mg, 0.1 mmol), 4-(bromomethyl)benzenesulfonamide (25.01 mg, 0.100mmol), and Pd(Ph₃P)₄ (11.56 mg, 10.00 μmol). The tube was sealed and airwas removed and re-filled with N₂ (2-3 times). A mixture of toluene(0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) was added, and then2N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added. The mixture wasstirred at 80° C. (pre-heated) for 2 h. The organic layer was separated,and the aqueous layer was extracted with EtOAc (2 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using30-60% EtOAc/hexane as the eluent to give ethyl2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(29 mg, 0.062 mmol, 61.9% yield) as a white solid.

Step 4: Synthesis of2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid (19)

To a solution of ethyl2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(26 mg, 0.055 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1N HCl_((aq)) (ca.0.6-0.65 mL) was added and until the pH ofaqueous layer was around 4. Then, hexane (5 mL) was added and theresulting solid was filtered, triturated with H₂O (1 ml×2), hexane (2mL×2), and dried to give2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 19 (21 mg, 0.048 mmol, 86% yield).

The compound was pure enough and was submitted (19 mg) to systemdirectly. ¹H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.21 (s, 2H),7.80-7.71 (m, 2H), 7.72-7.63 (m, 2H), 7.52-7.37 (m, 5H), 7.28 (s, 2H),4.15 (s. 2H); MS (M+H)⁺=441.

Example 29

This example describes the synthesis of2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 20 in an embodiment of the invention.

Step 1: Synthesis of 3-([1,1′-biphenyl]-3-yl)-1H-pyrazole

In a 2-neck flask was placed 3-(3-bromophenyl)-1H-pyrazole (1115 mg, 5mmol), phenylboronic acid (914 mg, 7.50 mmol), PdCl₂(dppf) (366 mg,0.500 mmol), and K₂CO₃ (2073 mg, 15.00 mmol). The air was removed andre-filled with N₂ (2-3 times). Then a mixture of 1,4-dioxane (12 ml,ratio: 2.000) and water (6 ml, ratio: 1.000) was added and stirred at95° C. (pre-heated) for 5 h. The organic layer was separated, and theaqueous layer was extracted with EtOAc (5 mL×2). The combined organiclayer was dried (Na₂SO₄) and filtered. After removal of the solvent, theproduct was purified by silica gel chromatography using 30-40-50%EtOAc/hexane as the eluent to give 3-([1,1′-biphenyl]-3-yl)-1H-pyrazole(1050 mg, 4.77 mmol, 95% yield).

Step 2: Synthesis of 3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazole

To a solution of 3-([1,1′-biphenyl]-3-yl)-1H-pyrazole (1050 mg, 4.77mmol) in DMF (7.5 ml) was added NBS (891 mg, 5.01 mmol). The mixture wasstirred at room temperature for 1 h. The mixture was poured intoEtOAc/H₂O/sat. Na₂CO_(3(aq)) (50 mL/30 mL/20 mL). The organic layer waswashed with H₂O (50 mL), dried (Na₂SO₄), and filtered. After removal ofthe solvent, the product was purified by silica gel chromatography using20-30% EtOAc/hexane as the eluent to give3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazole (1200 mg, 4.01 mmol, 84%yield).

Step 3: Synthesis of Ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (472mg, 2 mmol), 3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrrole (596 mg, 2.000mmol), and K₂CO₃ (415 mg, 3.00 mmol). The tube was sealed and DMSO (4ml) was added. The mixture was heated at 130° C. for 4 h. The mixturewas poured into H₂O (100 mL), and the solid was filtered, trituratedwith H₂O, and dried. The solid was dissolved in EtOAc and filtered. Theundissolved material was the hydrolized acid (21, ca. 110 mg with asmall amount of impurity). The filtrate was concentrated and trituratedwith ca. 5% EtOAc/hexane to give 420 mg of pure product. The solutionwas concentrated and combined with the extraction from the originalaqueous layer and then purified by silica gel chromatography using20-30% EtOAc/hexane as the eluent to give another 210 mg of product.Total 630 mg of ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylate(630 mg, 1.387 mmol, 69.3% yield) was obtained.

Step 4: Synthesis of Ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylate(454 mg, 1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381 mg,1.500 mmol), PdCl₂(dppf) (73.2 mg, 0.100 mmol), and potassium acetate(294 mg, 3.00 mmol). The tube was sealed and air was removed andre-filled with N₂ (2-3 times). Then, 1,4-dioxane (4 ml) was added andstirred at 95° C. (pre-heated) for overnight. The mixture was dilutedwith EtOAc and filtered through CELITE™ and eluted with EtOAc. Afterremoval of the solvent, the product was purified by silica gelchromatography using 10-25% EtOAc/hexane as the eluent to give product,which was triturated with a small amount of hexane and then dried togive ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(450 mg, 0.494 mmol, 49.4% yield) as solid. The product contained about45% of reduction (de-Br) product.

Step 5: Synthesis of Ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(91 mg, 0.1 mmol), 4-(bromomethyl)benzenesulfonamide (25.01 mg, 0.100mmol), and Pd(Ph₃P)₄ (11.56 mg, 10.00 μmol). The tube was sealed and airwas removed and re-filled with N₂ (2-3 times). A mixture of toluene(0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) was added, and then2N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added. The mixture wasstirred at 80° C. (pre-heated) for 2 h. The organic layer was separated,and the aqueous layer was extracted with EtOAc (2 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using30-60% EtOAc/hexane as the eluent to give ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate20 (35 mg, 0.064 mmol, 64.3% yield) as a white solid. Some of thereduction product (ca. 30 mg) from either the reaction and/or from aprevious step was collected and subjected to hydrolysis to give 22 (seeExample 31, Scheme 7A).

Step 6: Synthesis of2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid (20)

To a solution of ethyl2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(35 mg, 0.064 mmol) in THF (1 ml) was added LiOH(aq) (1.5 N in H₂O, 0.4mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1N HCl_((aq)) (ca. 0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2) and dried to give2-(3-([1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 20 (28 mg, 0.054 mmol, 84% yield).

The compound was pure enough and was submitted (24 mg) to systemdirectly. ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 8.29 (s, 1H), 8.24(s, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.80-7.74 (m, 2H), 7.74-7.67 (m, 2H),7.57 (d, J=7.6 Hz, 3H), 7.50-7.42 (m, 4H), 7.37 (dd, J=8.4, 6.3 Hz, 1H),7.30 (s, 2H), 4.21 (s, 2H); MS (M+H)⁺=517.

Example 30

This example describes the synthesis of2-(3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 21 in an embodiment of the invention.

The side product of step 3 in Example 28 was re-purified by reversephase chromatography to give2-(3-([1,1′-biphenyl]-3-yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 21. ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H). 8.93 (s, 1H),8.28 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.85 (dd, J=7.7, 1.5 Hz, 1H), 7.79(dd, J=7.9, 1.5 Hz, 1H), 7.72 (dd, J=7.5, 1.7 Hz, 2H), 7.63 (t, J=7.8Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 7.40 (t, J=7.4 Hz, 1H); MS (M+H)⁺=427

Example 31

This example describes the synthesis of2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,TFA 22 in an embodiment of the invention. See Scheme 7A.

To a solution of ethyl2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (30mg, 0.080 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O, 0.4mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added, and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2), and dried. The product still contained a small amount ofimpurity, which was dissolved in DMF, filtered through a filter, andsubmitted for purification to give2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,TFA 22 (0.8 mg, 1.734 μmol, 2.170% yield). MS (M+H)⁺=348.

Example 32

This example describes the synthesis of2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid, TFA 23 in an embodiment of the invention.

Step 1: Synthesis of 3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine

In a 2-neck flask was placed 3-bromo-1H-pyrrolo[2,3-b]pyridine (788 mg,4 mmol), (3,4-difluorophenyl)boronic acid (758 mg, 4.80 mmol),PdCl₂(dppf) (146 mg, 0.200 mmol), and K₂CO₃ (1658 mg, 12.00 mmol). Theair was removed and re-filled with N₂ (2-3 times). Then a mixture of1,4-dioxane (12 ml, ratio: 2.000) and water (6 ml, ratio: 1.000) wasadded and stirred at 95° C. (pre-heated) for 3 h. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (5 mL×2). Thecombined organic was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using30-40% EtOAc/hexane as the eluent to give3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine (260 mg, 1.129 mmol,28.2% yield).

Step 2: Synthesis of Tert-Butyl2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate

In a microwave tube was placed3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine (50.6 mg, 0.220 mmol),tert-butyl 2-bromothiazole-4-carboxylate (52.8 mg, 0.2 mmol),(1S,2S)—N¹,N²-dimethylcyclohexane-1,2-diamine (5.69 mg, 0.040 mmol), CuI(3.81 mg, 0.020 mmol), and K₃PO₄ (127 mg, 0.600 mmol). The air wasremoved and re-filled with N₂ (3 times). Then toluene (2 ml) was addedand the mixture was stirred at 110° C. for overnight. After cooling toroom temperature, the mixture was diluted with EtOAc (3 mL) and filteredthrough celite and eluted with EtOAc. The filtrate was concentrated andthe mixture was purified by silica gel chromatography using 10-30%EtOAc/hexane as the eluent to give tert-butyl2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(75 mg, 0.181 mmol, 91% yield). This material contained some Br-startingmaterial and impurity was used for de-protection and purified in thenext step.

Step 3: Synthesis of2-(3-(3-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicAcid, TFA (23)

To a solution of tert-butyl2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(75 mg, 0.181 mmol) in 1,4-dioxane (1 ml) was added HCl (4M in dioxane,1 mL, 4 mmol). The mixture was stirred at room temperature for 2 h. Themixture was concentrated and the crude material was dissolved in DMF,filtered through a filter, and submitted for purification to give2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid, TFA 23 (1.6 mg, 3.39 mol, 1.871% yield). MS (M+H)⁺=358.

Example 33

This example describes the synthesis of2-(5-hydroxy-3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 24 in an embodiment of the invention.

Step 1: Synthesis of Ethyl3-oxo-3-phenyl-2-(4-sulfamoylphenoxy)propanoate

To a mixture of sodium 4-sulfamoylphenolate (195 mg, 1 mmol) and ethyl2-bromo-3-oxo-3-phenylpropanoate (298 mg, 1.100 mmol) was added EtOH (1ml). The mixture was stirred at room temperature for 30 min. The mixturewas concentrated and purified by silica gel chromatography using 30-50%EtOAc/hexane as the eluent to give ethyl3-oxo-3-phenyl-2-(4-sulfamoylphenoxy)propanoate (66 mg, 0.182 mmol,18.16% yield).

Step 2: Synthesis of Give2-(5-hydroxy-3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid, TFA (24)

In a microwave tube was placed ethyl3-oxo-3-phenyl-2-(4-sulfamoylphenoxy)propanoate (66 mg, 0.182 mmol),ethyl 2-hydrazinylthiazole-4-carboxylate (34.0 mg, 0.182 mmol), andp-TsOH (34.5 mg, 0.182 mmol) and added EtOH (2 ml). The tube was sealedand heated at 150° C. for 20 min. The solvent was removed via airblow-down and then added THF (1 mL) and 1.5 N LiOH_((aq)) (1 mL, 1.5mmol). The mixture was stirred at room temperature for 1 h. Then 1 NHCl_((aq)) (ca. 1.5-1.55 mL) was added (pH of aqueous layer is ca. 3),and the aqueous layer was extracted with EtOAc (3 mL×4). The combinedorganic layer was dried (Na₂SO₄), filtered, and concentrated. The crudeproduct was dissolved in DMF and submitted for purification to give2-(5-hydroxy-3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 24 (20.8 mg, 0.036 mmol, 20.00% yield). MS (M+H)⁺=459

Example 34

This example describes the synthesis of2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylicacid 25 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (472mg, 2 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (515 mg, 2.100 mmol), andK₂CO₃ (304 mg, 2.200 mmol). The tube was sealed and DMSO (2 ml) wasadded. The mixture was heated at 140° C. for 2 h. The mixture was pouredinto EtOAc/H₂O (30 ml/30 mL). The organic layer was dried (Na₂SO₄) andfiltered. After removal of the solvent, the product was purified bysilica gel chromatography using 30-50-80% EtOAc/hexane as the eluent togive ethyl2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate (328 mg,0.820 mmol, 41.0% yield).

Step 2: Synthesis of Ethyl2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate

In a 2-neck flask was placed ethyl2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate (40.0mg, 0.1 mmol), (3,4-difluorophenyl)boronic acid (31.6 mg, 0.200 mmol),PdCl₂(dppf) (7.32 mg, 10.00 μmol), and K₂CO₃ (69.1 mg, 0.500 mmol). Theair was removed and re-filled with N₂ (2-3 times). Then a mixture of1,4-dioxane (1 mL, ratio: 2.000) and water (0.5 ml, ratio: 1.000) wasadded and stirred at 95° C. (pre-heated) for 3 h. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (5 mL×3). Thecombined organic layer was dried (Na₂SO₄) and filtered. After removal ofthe solvent, the product was purified by silica gel chromatography using40-70% EtOAc/hexane as the eluent to give ethyl2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate(11 mg, 0.028 mmol, 28.5% yield).

Step 3: Synthesis of2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylicAcid (25)

To a solution of ethyl2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate(10 mg, 0.026 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added, and the resultingsolid was filtered, triturated with hexane (2 mL×2), and dried to give2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylicacid 25 (6 mg, 0.017 mmol, 64.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.16 (s, 1H), 8.88-8.78 (m, 2H), 8.33 (s, 1H), 8.15 (ddd, J=11.7, 7.7,2.2 Hz. 1H), 8.05-7.97 (m, 1H), 7.68 (dt, J=10.8, 8.5 Hz, 1H), 7.60 (dd,J=8.1, 4.6 Hz, 1H); MS (M+H)⁺=359.

Example 35

This example describes the synthesis of2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid 26 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (944mg, 4 mmol), 3-bromo-1H-pyrrolo[2,3-b]pyridine (867 mg, 4.40 mmol), andK₂CO₃ (663 mg, 4.80 mmol). The tube was sealed and DMSO (7.5 ml) wasadded. The mixture was heated at 150° C. for 3 h. The mixture was pouredinto EtOAc/H₂O (30 mL/30 mL). The organic was dried (Na₂SO₄) andfiltered. After removal of the solvent, the product was purified (twice)by silica gel chromatography using 10-20% EtOAc/hexane as the eluent togive ethyl2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate (587 mg,1.667 mmol, 41.7% yield).

Step 2: Synthesis of Ethyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate (352 mg,1 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(330 mg, 1.300 mmol), PdCl₂(dppf) (73.2 mg, 0.100 mmol), and AcOK (294mg, 3.00 mmol). The tube was sealed and air was removed and re-filledwith N₂ (2-3 times). Then, 1,4-dioxane (3 ml) was added and stirred at95° C. (pre-heated) for overnight. The mixture was diluted with EtOAcand filtered through CELITE™ and eluted with EtOAc. After removal of thesolvent, the product was purified by silica gel chromatography using10-25% EtOAc/hexane as the eluent to give product, which was trituratedwith a small amount of hexane to give ethyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(293 mg, 0.734 mmol, 73.4% yield) as solid.

Step 3: Synthesis of Ethyl2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(39.9 mg, 0.1 mmol), 4-(bromomethyl)benzenesulfonamide (25.01 mg, 0.100mmol), and Pd(Ph₃P)₄ (11.56 mg, 10.00 μmol). The tube was sealed and airwas removed and re-filled with N₂ (2-3 times). A mixture of toluene(0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) was added, and then2N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added. The mixture wasstirred at 80° C. (pre-heated) for 2 h. The organic layer was separated,and the aqueous layer was extracted with EtOAc (2 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using30-80% EtOAc/hexane as the eluent to give ethyl2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(28 mg, 0.063 mmol, 63.3% yield) as a white solid.

Step 4: Synthesis of2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicAcid (26)

To a solution of ethyl2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(28 mg, 0.063 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2), and dried to give2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid 26 (21 mg, 0.051 mmol, 80% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.04 (s, 1H), 8.46 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (s, 1H), 8.09 (dd,J=7.8, 1.5 Hz, 1H), 8.07 (s, 1H), 7.80-7.72 (m, 2H), 7.58 (d, J=8.2 Hz,2H), 7.32 (dd, J=7.9, 4.8 Hz, 1H), 7.27 (s, 2H), 4.23 (s, 2H); MS(M+H)+=415.

Example 36

This example describes the synthesis of2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 27 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(70.9 mg, 0.1 mmol), 1-(bromomethyl)-4-(methylsulfonyl)benzene (24.91mg, 0.100 mmol), and Pd(Ph₃P)₄ (11.56 mg, 10.00 μmol). The tube wassealed and air was removed and re-filled with N₂ (2-3 times). A mixtureof toluene (0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) wasadded, and then 2N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added.The mixture was stirred at 80° C. (pre-heated) for 2 h. The organiclayer was separated, and the aqueous layer was extracted with EtOAc (2mL×3). The combined organic layer was dried (Na₂SO₄) and filtered. Afterremoval of the solvent, the product was purified by silica gelchromatography using 25-50% EtOAc/hexane as the eluent to give ethyl2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(35 mg, 0.075 mmol, 74.9% yield) as a white solid.

Step 2: Synthesis of2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid (27)

To a solution of ethyl2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(35 mg, 0.075 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2), and dried to give2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 27 (30 mg, 0.068 mmol, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.17 (s, 1H), 8.34 (s, 1H), 8.23 (d, J=1.7 Hz, 1H), 7.86-7.79 (m, 2H),7.70-7.62 (m, 2H), 7.53-7.37 (m, 5H), 4.19 (s, 2H), 3.17 (s, 3H); MS(M+H)⁺=440.

Example 37

This example describes the synthesis of2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 28 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(70.9 mg, 0.1 mmol), 1-(bromomethyl)-4-(trifluoromethyl)benzene (23.90mg, 0.100 mmol), and Pd(Ph₃P)₄ (11.56 mg, 10.00 μmol). The tube wassealed and air was removed and re-filled with N2 (2-3 times). A mixtureof toluene (0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) wasadded, and then 2 N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added.The mixture was stirred at 80° C. (pre-heated) for 2 h. The organiclayer was separated, and the aqueous layer was extracted with EtOAc (2mL×3). The combined organic layer was dried (Na₂SO₄) and filtered. Afterremoval of the solvent, the product was purified by silica gelchromatography using 10-25% EtOAc/hexane as the eluent to give ethyl2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(58 mg, 0.070 mmol, 69.7% yield) as a white solid. This material wasmixed with the reduction product and was used for hydrolysis directlyand purified at the next step.

Step 2: Synthesis of2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid, TFA (28)

To a solution of ethyl2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(58 mg, 0.070 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added, and the pH of aqueouslayer was around 4. Then, the mixture was concentrated and the residuewas dissolved in DMF, filtered through a filter and submitted forpurification to give2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 28 (13 mg, 0.024 mmol, 34.3% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 13.17 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.69-7.59 (m, 4H),7.50-7.36 (m, 5H), 4.18 (s, 2H); MS (M+H)⁺=430.

Example 38

This example describes the synthesis of2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid, TFA 29 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate

In a 2-neck flask was placed ethyl2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate (35.2mg, 0.1 mmol), [1,1′-biphenyl]-3-ylboronic acid (39.6 mg, 0.200 mmol),PdCl₂(dppf) (7.32 mg, 10.00 μmol), and K₂CO₃ (69.1 mg, 0.500 mmol). Theair was removed and re-filled with N₂ (2-3 times). Then a mixture of1,4-dioxane (1 mL, ratio: 2.000) and water (0.5 ml, ratio: 1.000) wasadded and stirred at 95° C. (pre-heated) for 3 h. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (5 mL×3). Thecombined organic layer was dried (Na₂SO₄) and filtered. After removal ofthe solvent, the product was purified by silica gel chromatography using40-70% EtOAc/hexane as the eluent to give ethyl2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(30 mg, 0.053 mmol, 52.9% yield). This product contained some impurityand was used for the next step without further purification.

Step 2: Synthesis of2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicAcid, TFA (29)

To a solution of ethyl2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate(30 mg, 0.071 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H2O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 3 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. The mixture was concentrated and the residue wasdissolved in DMF, filtered through a filter, and submitted forpurification to give2-(3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylicacid, TFA 29 (2.1 mg, 4.11 mol, 5.82% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 13.08 (s, 1H), 8.68 (s, 1H). 8.57 (d, J=4.7 Hz, 1H), 8.55-8.50 (m,1H), 8.28 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.83 (m, 3H), 7.68 (d, J=7.7Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.54-7.44 (m, 3H), 7.43-7.35 (m, 1H);MS (M+H)⁺=398.

Example 39

This example describes the synthesis of2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 30 in an embodiment of the invention.

Step 1: Synthesis of (3-bromo-1H-indol-5-yl)(morpholino)methanone

To a mixture of 3-bromo-1H-indole-5-carboxylic acid (960 mg, 4 mmol) andHATU (2281 mg, 6.00 mmol) was added DMF (5 ml) and then morpholine (697mg, 8.00 mmol) and Hünig's base (1.048 nil, 6.00 mmol). The mixture wasstirred at room temperature for 1.5 h. The mixture was poured intoEtOAc/H₂O (60 mL/60 mL). The organic layer was dried (Na₂SO₄) andfiltered. After removal of the solvent, the product was purified bysilica gel chromatography using 50-100% EtOAc/hexane as the eluent togive (3-bromo-1H-indol-5-yl)(morpholino)methanone (1204 mg, 3.89 mmol,97% yield).

Step 2: Synthesis of Ethyl2-(3-bromo-5-(morpholine-4-carbonyl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (425mg, 1.800 mmol), (3-bromo-1H-indol-5-yl)(morpholino)methanone (464 mg,1.5 mmol), and K₂CO₃ (415 mg, 3.00 mmol). The tube was sealed and DMSO(3 ml) was added. The mixture was heated at 125° C. for overnight. Themixture was poured into vigorously stirred H₂O (100 mL) and the solidwas filtered, triturated with H₂O, and dried. To the solid was addedhexane (30 mL), and the mixture was sonicated and filtered. The solidwas dried to give ethyl2-(3-bromo-5-(morpholine-4-carbonyl)-1H-indol-1-yl)thiazole-4-carboxylate(485 mg, 1.045 mmol, 69.6% yield).

Step 3: Synthesis of Ethyl2-(5-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-bromo-5-(morpholine-4-carbonyl)-1H-indol-1-yl)thiazole-4-carboxylate(464 mg, 1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381 mg,1.500 mmol), PdCl₂(dppf) (73.2 mg, 0.100 mmol), and potassium, acetate(294 mg, 3.00 mmol). The tube was sealed and air was removed andre-filled with N₂ (2-3 times). Then, 1,4-dioxane (3 ml) was added andstirred at 95° C. (pre-heated) for overnight. The mixture was dilutedwith EtOAc and filtered through CELITE™ and eluted with EtOAc. Afterremoval of the solvent, the product was purified by silica gelchromatography using 40-100% EtOAc/hexane as the eluent to give product,which was triturated with a small amount of hexane to give ethyl2-(5-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate(360 mg, 0.669 mmol, 66.9% yield) as solid. This material contained avery small amount of reduction (de-Br) product, ˜5%, and was usedwithout further purification.

Step 4: Synthesis of Ethyl2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(5-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate(77 mg, 0.15 mmol), 4-(bromomethyl)benzenesulfonamide (49.9 mg, 0.200mmol), and Pd(Ph₃P)₄ (17.33 mg, 0.015 mmol). The tube was sealed and airwas removed and re-filled with N₂ (2-3 times). A mixture of toluene(0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) was added, and then2 N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 4 equiv) was added. The mixture wasstirred at 80° C. (pre-heated) for 2 h. The organic layer was separated,and the aqueous layer was extracted with EtOAc (2 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using90-100% EtOAc/hexane as the eluent to give ethyl2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(70 mg, 0.126 mmol, 84% yield) as a white solid.

Step 5: Synthesis of2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicAcid (30)

To a solution of ethyl2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(65 mg, 0.117 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added, and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2), and dried. The solid was collected and 10% CH₂Cl₂/hexane (15 mL)was added, and the mixture was sonicated and filtered. The solid wasdried to give2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 30 (19 mg, 0.036 mmol, 30.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.20 (s, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.73(d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.6Hz, 1H), 7.25 (s, 2H), 4.21 (s, 2H), 3.76-3.34 (m, 8H); MS (M+H)⁺=527.

Example 40

This example describes the synthesis of2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 31 in an embodiment of the invention.

Step 1: Synthesis of 3-bromo-5-fluoro-1H-indole

To a solution of 5-fluoro-1H-indole (1351 mg, 10 mmol) in CHCl₃ (10 ml)and pyrdine (1.779 ml, 22.00 mmol) at 0° C. was added NBS (1958 mg,11.00 mmol). The mixture was stirred at 0° C. for 2 h. The mixture wasconcentrated to remove most of the solvent. The residue was dissolved inEtOAc (50 mL) and the organic layer washed 0.5 N HCl_((aq)) (50 mL), H₂O(50 mL), 2 N Na₂CO_(3(aq)) (50 mL), H₂O (50 mL), dried (Na₂SO₄), andfiltered. The product was checked by LCMS and was dried to give3-bromo-5-fluoro-1H-indole (1945 mg, 9.09 mmol, 91% yield). Thismaterial was used for the next step without further purification.

Step 2: Synthesis of Ethyl2-(3-bromo-5-fluoro-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (708mg, 3 mmol), 3-bromo-5-fluoro-1H-indole (642 mg, 3.00 mmol), and K₂CO₃(829 mg, 6.00 mmol). The tube was sealed and DMSO (4 ml) was added. Themixture was heated at 125° C. for 5 h. The mixture was poured intovigorously stirred H₂O (100 mL) and the solid was filtered, trituratedwith H₂O and then hexane, and dried to give ethyl2-(3-bromo-5-fluoro-1H-indol-1-yl)thiazole-4-carboxylate (800 mg, 2.167mmol, 72.2% yield).

Step 3: Synthesis of Ethyl2-(5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-bromo-5-fluoro-1H-indol-1-yl)thiazole-4-carboxylate (554 mg, 1.5mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (571mg, 2.250 mmol), PdCl₂(dppf) (110 mg, 0.150 mmol), and potassium acetate(442 mg, 4.50 mmol). The tube was sealed and air was removed andre-filled with N₂ (2-3 times). Then, 1,4-dioxane (4 ml) was added andstirred at 95° C. (pre-heated) for overnight. The mixture was dilutedwith EtOAc and filtered through CELITE™ and eluted with EtOAc. Afterremoval of the solvent, the product was purified by silica gelchromatography using 5-20% EtOAc/hexane as the eluent to give product,which was triturated with a small amount of hexane to give ethyl2-(5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate(730 mg, ca. 55% purity, 0.965 mmol, 64.3% yield) as solid. Thismaterial contained reduction (de-Br) product, ˜45%.

Step 4: Synthesis of Ethyl2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate(114 mg, 0.15 mmol, ˜55% purity), 4-(bromomethyl)benzenesulfonamide(49.9 mg, 0.200 mmol), and Pd(Ph₃P)₄ (17.33 mg, 0.015 mmol). The tubewas sealed and air was removed and re-filled with N₂ (2-3 times). Amixture of toluene (0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000)was added, and then 2 N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 4 equiv) wasadded. The mixture was stirred at 80° C. (pre-heated) for 2 h. Theorganic layer was separated, and the aqueous layer was extracted withEtOAc (2 mL×3). The combined organic layer was dried (Na₂SO₄) andfiltered. After removal of the solvent, the product was purified bysilica gel chromatography using 20-50% EtOAc/hexane as the eluent togive ethyl2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(47 mg, 0.102 mmol, 68.2% yield) as a white solid.

Step 5: Synthesis of2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicAcid (31)

To a solution of ethyl2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(47 mg, 0.102 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2) and dried to give2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 31 (37 mg, 0.086 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.17 (s, 1H), 8.40 (dd, J=9.2, 4.5 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H),7.93 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.37 (dd,J=9.2, 2.6 Hz, 1H), 7.27-7.18 (m, 3H), 4.16 (s, 2H); MS (M+H)⁺=432.

Example 41

This example describes the synthesis of2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 32 in an embodiment of the invention.

Step 1: Synthesis of 4-((3-bromo-1H-indol-5-yl)methyl)morpholine

To a solution of (3-bromo-1H-indol-5-yl)(morpholino)methanone (711 mg,2.3 mmol) in CH₂Cl₂ (5 ml) under N₂ at 0° C. was added DIBAL-H (1636 mg,11.50 mmol) (1 M in THF, 11.5 mL). After addition of DIBAL-H, themixture was allowed to warm to room temperature for 2 h. The mixture wasslowly poured into vigorously stirred sat. Rochelle salt solution (aq.)(15 mL) was added, and the mixture was stirred for 30 min. The aqueouslayer was extracted with CH₂Cl₂ (10 mL×2). The combined organic layerwas dried (Na₂SO₄) and filtered. After removal of the solvent, theproduct was purified by silica gel chromatography using 50-100%EtOAc/hexane as the eluent to give4-((3-bromo-1H-indol-5-yl)methyl)morpholine (477 mg, 1.616 mmol, 70.3%yield).

Step 2: Synthesis of Ethyl2-(3-bromo-5-(morpholinomethyl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (443mg, 1.875 mmol), 4-((3-bromo-1H-indol-5-yl)methyl)morpholine (443 mg,1.5 mmol), and K₂CO₃ (311 mg, 2.250 mmol). The tube was sealed and DMSO(2 ml) was added. The mixture was heated at 125° C. for 3 h. The mixturewas poured into EtOAc/H₂O (50 mL/50 mL). The aqueous layer was extractedwith EtOAc (50 mL×2). The combined organic layer was dried (Na₂SO₄) andfiltered. After removal of the solvent, the product was purified bysilica gel chromatography using 40-100% EtOAc/hexane as the eluent togive ethyl2-(3-bromo-5-(morpholinomethyl)-1H-indol-1-yl)thiazole-4-carboxylate(426 mg, 0.946 mmol, 63.1% yield).

Step 3: Synthesis of Ethyl2-(5-(morpholinomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-bromo-5-(morpholinomethyl)-1H-indol-1-yl)thiazole-4-carboxylate(426 mg, 0.946 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (480 mg,1.892 mmol), PdCl₂(dppf) (69.2 mg, 0.095 mmol), and potassium acetate(371 mg, 3.78 mmol). The tube was sealed and air was removed andre-filled with N₂ (2-3 times). Then, 1,4-dioxane (2 ml) was added andstirred at 95° C. (pre-heated) for 5 h. The mixture was diluted withEtOAc and filtered through celite and eluted with EtOAc. After removalof the solvent, the product was purified by silica gel chromatographyusing 50-100% EtOAc/hexane as the eluent to give ethyl2-(5-(morpholinomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylateas solid.

Step 4: Synthesis of Ethyl2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(5-(morpholinomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate(99 mg, 0.2 mmol), 4-(bromomethyl)benzenesulfonamide (50.0 mg, 0.2mmol), and Pd(Ph₃P)₄ (23.11 mg, 0.020 mmol). The tube was sealed and airwas removed and re-filled with N₂ (2-3 times). A mixture of toluene(0.75 ml, ratio: 2.500)/EtOH (0.3 ml, ratio: 1.000) was added, and then2 N Na₂CO_(3(aq)) (0.3 mL, 0.6 mmol, 6 equiv) was added. The mixture wasstirred at 80° C. (pre-heated) for 2 h. The organic layer was separated,and the aqueous layer was extracted with EtOAc (2 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of thesolvent, the product was purified by silica gel chromatography using60-100% EtOAc/hexane as the eluent to give ethyl2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(37 mg, 0.068 mmol, 34.2% yield).

Step 5: Synthesis of2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicAcid (32)

To a solution of ethyl2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylate(37 mg, 0.068 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1 N HCl_((aq)) (ca.0.6 mL) was added and the pH of aqueous layerwas around 6. Then, hexane (5 mL) was added and the solid was filtered,triturated with H₂O (1 ml×2) and then hexane (2 mL×2), and dried to give2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid 32 (23 mg, 0.045 mmol, 65.6% yield). MS (M+H)⁺=513.

Example 42

This example describes the synthesis of2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 33 in an embodiment of the invention.

Step 1: Synthesis of 4-(2-oxo-2-phenylethoxy)benzenesulfonamide

To a mixture of 4-hydroxybenzenesulfonamide (520 mg, 3.00 mmol) andK₂CO₃ (551 mg, 3.99 mmol) was added acetone (10 mL) and stirred at roomtemperature for 30 min. Then 2-bromo-1-phenylethanone (597 mg, 3 mmol)in acetone (5 mL) was added. The mixture was stirred at room temperaturefor 20 h. Then, H₂O (15 mL) and hexane (20 mL) were added to thereaction mixture. The solid was filtered and washed with H₂O (2 mL×2)and then 5% EtOAc/hexane (5 mL×3). The solid was dried to give4-(2-oxo-2-phenylethoxy)benzenesulfonamide (804 mg, 2.76 mmol, 92%yield) as a white solid.

Step 2: Synthesis of 4-((3-phenyl-1H-pyrazol-4-yl)oxy)benzenesulfonamide

In a microwave tube was placed4-(2-oxo-2-phenylethoxy)benzenesulfonamide (291 mg, 1 mmol) and1,1-dimethoxy-N,N-dimethylmethanamine (1.5 ml, 11.29 mmol) (neat). Thetube was sealed and heated at 90° C. for overnight. The mixture wasconcentrated by blowing air and the residue was dried in vacuo for hoursto give crude mixture of4-((1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)oxy)benzenesulfonamide(maybe some isomer or aldehyde). To the crude intermediate was addedEtOH (4 mL) and N₂H₄ monohydrate (MW=50, d=1.032, 0.145 mL, 3 mmol). Themixture was sealed and heated at 60° C. for 4 h. After cooling to roomtemperature, the solvent was removed by blowing air, and the residue waspurified by silica gel chromatography using 40-80% EtOAc/hexane as theeluent to give 4-((3-phenyl-1H-pyrazol-4-yl)oxy)benzenesulfonamide (85mg, 0.270 mmol, 27.0% yield) (2 steps). This material contained someimpurity and was used for the next step without further purification.

Step 3: Synthesis of Ethyl2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl 2-bromothiazole-4-carboxylate (70.0mg, 0.296 mmol), 4-((3-phenyl-1H-pyrazol-4-yl)oxy)benzenesulfonamide (85mg, 0.270 mmol), and potassium carbonate (55.9 mg, 0.404 mmol). The tubewas sealed and DMSO (1.5 ml) was added. The mixture was heated at 120°C. for 3 h. The mixture was poured into EtOAc/H₂O (30 mL/30 mL). Theaqueous layer was extracted with EtOAc (30 mL). The combined organiclayer was dried (Na₂SO₄) and filtered. After removal of the solvent, theproduct was purified by silica gel chromatography using 30-50-60%EtOAc/hexane as the eluent to give ethyl2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate(35 mg, 0.074 mmol, 27.6% yield).

Step 4: Synthesis of2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid (33)

To a solution of ethyl2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate(32 mg, 0.068 mmol) in THF (1 ml) was added LiOH_((aq)) (1.5 N in H₂O,0.4 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 h.Then, 1N HCl_((aq)) (ca.0.6-0.65 mL) was added and the pH of aqueouslayer was around 4. Then, hexane (5 mL) was added and the resultingsolid was filtered, triturated with H₂O (1 ml×2) and then hexane (2mL×2), and dried to give2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 33 (21 mg, 0.047 mmol, 69.8% yield).

Example 43

This example describes the synthesis of2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)thiazole-4-carboxylicacid, NH₃ 34 in an embodiment of the invention.

According to similar procedures described above for 26, the titlecompound was prepared starting from 3-bromo-1H-pyrrolo[3,2-c]pyridine,and the final product was purified by reverse phase HPLC chromatographyunder basic conditions to give2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)thiazole-4-carboxylicacid, NH₃ 34 (NH₃ salt). MS (M+H)⁺=415.

Example 44

This example describes the synthesis of2-(3-(4-sulfamoylbenzyl)-1H-indazol-1-yl)thiazole-4-carboxylic acid (35)in an embodiment of the invention.

According to similar procedures described above for 26, the titlecompound was prepared starting from 3-bromoindazole to give2-(3-(4-sulfamoylbenzyl)-1H-indazol-1-yl)thiazole-4-carboxylic acid 35.¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.18(s, 1H), 7.80 (dd, J=8.0, 1.0 Hz, 1H), 7.77-7.72 (m, 2H), 7.67 (ddd,J=8.3, 7.0, 1.1 Hz, 1H), 7.59-7.51 (m, 2H), 7.35 (ddd, J=8.1, 7.0, 0.9Hz, 1H), 7.27 (s, 2H), 4.49 (s, 2H); MS (M+H)⁺=415.

Example 45

This example describes the synthesis of2-(3-(4-sulfamoylbenzyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indol-1-yl)thiazole-4-carboxylicacid, NH₃ 36 in an embodiment of the invention.

Step 1: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indole

To a mixture of 1H-indol-5-ol (0.799 g, 6 mmol),tetrahydro-2H-pyran-4-ol (0.919 g, 9.00 mmol), and PPh₃ (2.361 g, 9.00mmol) in THF (10 ml) under N₂ was added a solution of (E)-di-tert-butyldiazene-1,2-dicarboxylate (2.072 g, 9.00 mmol) in THF (6 mL). Themixture was then stirred at 50° C. for 3 h. Tetrahydropyran-4-ol (3mmol) was added and then a solution of PPh₃ (3 mmol) and(E)-di-tert-butyl diazene-1,2-dicarboxylate (3 mmol) in THF (5 mL) wasadded. The mixture was stirred at 50° C. for another 3 h. The mixturewas concentrated, and the residue was purified by silica gelchromatography using 20-40% EtOAc/hexane as the eluent to give5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indole (1.18 g, 5.43 mmol, 91%yield).

Step 2: Synthesis of2-(3-(4-sulfamoylbenzyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indol-1-yl)thiazole-4-carboxylicAcid, NH₃ (36)

According to similar procedures described above for 31, the titlecompound was prepared starting from5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indole and the final product waspurified by reverse phase HPLC chromatography under basic condition togive2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)thiazole-4-carboxylicacid, NH₃ 36 (NH₃ salt). MS (M+H)⁺=514.

Example 46

This example describes the synthesis of2-(6-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid, NH₃ 37 in an embodiment of the invention.

Step 1: Synthesis of 3-bromo-1H-indole-6-carboxylic Acid

To a solution of methyl 3-bromo-1H-indole-6-carboxylate (1.270 g, 5mmol) in THF (10 ml, ratio: 10.00) was added LiOH(aq) (1.5 N in H₂O, 12mL, 18 mmol). The mixture was stirred at room temperature for 2 h. Then,1N HCl(aq) was added and the pH of aqueous layer was around 4. Then,hexane (30 mL) was added and the resulting solid was filtered,triturated with H₂O (3 ml×2) and then hexane (5 mL×2), and dried to give3-bromo-1H-indole-6-carboxylic acid (1.136 g, 4.73 mmol, 95% yield).

Step 2: Synthesis of2-(6-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicAcid, NH₃ 37

According to similar procedures described above for 30, the titlecompound was prepared starting from 3-bromo-1H-indole-6-carboxylic acidand the final product was purified by reverse phase HPLC chromatographyunder basic condition to give2-(6-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carboxylicacid, NH₃ 37 (NH₃ salt). MS (M+H)⁺=527.

Example 47

This example describes the synthesis of1-(1H-benzo[d][1,2,3]triazol-1-yl)-ketones in an embodiment of theinvention.

To a solution of 1H-benzo[d][1,2,3]triazole (4000 mmol) in CH₂Cl₂ wasadded thionyl chloride (SOCl₂, 1000 mmol) and stirred at rt for 0.5 h.Alkyl carboxylic acid (1000 mmol) was then added and the reactionmixture was stirred for 2 h. Upon completion as detected by LCMS, thereaction mixture was filtered and the filter cake was washed withCH₂Cl₂. The filtrate was neutralized with bicarbonate solution slowlyand stirred for 30 minutes then transfered to a separatory funnel. Theorganic layer washed with bicarbonate solution then with brine, driedover Na₂SO₄, filtered, and concetrated. The residue was purifieddirectly on silica using organic gradient (0-20% ethyl acetate inhexanes over 10 CV). The first peak was collected and dried to get anoil or solid.

Example 48

This example describes the synthesis of4-(bromomethyl)benzenesulfonamides in an embodiment of the invention.

Step 1: Synthesis of 4-methylbenzenesulfonamide Derivatives

A stirring solution of 4-methylbenzene-1-sulfonyl chloride (95 g, 455mmol) in CH₂Cl₂ was bubbled with ammonia for 45 minutes. The reactionmixture was then filtered. The filtrate was concentrated and dried underreduced pressure. The resulting off-white powder was taken to the nextstep without further purification or characterization; (M+H)⁺=190

Step 2: Synthesis of 4-(bromomethyl)benzenesulfonamide Derivatives

A stirring solution of 4-methyl-2 or 3-fluorobenzenesulfonamide (7.3mmol), N-bromosuccinimide (NBS 9.5 mmol) and AIBN (0.73 mmol) in CCl₄(Volume: 20 mL) was refluxed for 24 h. The solvent was evaporated andthe residue was suspended in ethyl acetate and filtered. The filtratewas washed with Na₂S₂O₃, NaHCO₃ and brine solutions, dried over Na₂SO₄,and filtered. Silica gel was added and the solvent was removed underreduced pressure. The dry loaded product was purified on silica usinggradient elution (5-100% ethyl acetate in hexanes over 16 CV in a 120 gsilica column) The pale colorless produced was used in the next stepwithout further purification or characterization;

Example 49

This example describes the synthesis of2-(5-(alkyl)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids and2-(3-(alkyl)-5-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids in an embodiment of the invention.

Step 1: Synthesis of 1-phenyl-3-alkyl-1,3-diones

To a stirring solution of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-alkylketone (200 mmol) and magnesium bromide diethyl etherate (413 mmol) inCH₂Cl₂ was added 1-phenylethanone derivatives (165 mmol). Diisopropylethyl amine (500 mmol) was added dropwise over several minutes and thereaction mixture was stirred at rt for 2 h. Upon completion as detectedby LCMS, the reaction was slowly quenched with 1.0 M HCl and washed with1.0 M HCl and brine. The residue was dried over Na₂SO₄, filtered, andconcetrated under reduced pressure. The residue was purified directly onsilica using gradient elution (0-30% ethyl acetate in hexanes over 20CV). The resulting oils were used in the next step without furtherpurification or characterization.

Step 2: Synthesis of 4-(2-benzoyl-3-oxo)-3-alkyl-benzenesulfonamides

1-phenyl-3-alkyl-1,3-diones (150 mmol) and cesium carbonate (Cs₂CO₃, 226mmol) were dissolved in DMSO (50 ml). The reaction mixture was stirredat rt for 10 minutes at which time potassium iodide were added (KI, 150mmol) and 4-(bromomethyl)-benzenesulfonamides (165 mmol). The resultingmixture was stirred at rt for 1 h. Upon completion as detected by LCMS,the reaction mixture was diluted with a large excess of ethyl acetateand filtered through celite. The filtrate was washed with 1 M HCl, sataq NH₄Cl and brine, dried over Na₂SO₄, filtered, and concetrated underreduced pressure. The residue was purified directly on silica usinggradient elution (20-40% ethyl acetate in hexanes over 16 CV).

Step 3: Ethyl2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates

Method A—A solution of 4-(2-benzoyl-3-oxo)-3-alkyl-benzenesulfonamide(6.7 mmol), ethyl 2-hydrazinylthiazole-4-carboxylate, 2 HBr (7.3 mmol)and p-toluene sulfonic acid (pTsOH, 20 mmol) in dioxane was heated in asealed vessel in the microwave for 15 min at 160° C. Upon completion asdetected by LCMS, the reaction mixture was diluted with ethyl acetateand filtered through celite. The solvent was removed under reducedpressure and the crude product was purified directly on silica usinggradient elution (0-100% ethyl acetate in hexanes over 15 CV).

Method B—A solution of 4-(2-(benzoyl)-3-oxo-3-alkyl-benzenesulfonamide(113 mmol), p-toluene sulfonic acid (pTsOH, 57 mmol) and pyrrolidine (57mmol) in ethanol was stirred at 100° C. for 1 h, after which time ethyl2-hydrazinylthiazole-4-carboxylate, 2 HBr (136 mmol) was added. Theresulting reaction mixture was refluxed overnight. Upon completion asdetected by LCMS, the solvent was removed under reduced pressure and theresidue was purified without work-up directly on silica using gradientelution (20-40% ethyl acetate in hexanes over 20 CV). A mixture ofregioisomers were collected as a single peak. After removing thesolvent, the regioisomers were separated via reverse phase preparativecolumn using gradient elution (50-100% acetonitrile modified with 0.1%TFA in water modified with 0.1% TFA over 25 CV). The second elution peakwas pooled and concentrated, and the resulting solid was stirred with aclear solution of NaHCO₃. The precipitate was collected by filtration,washed with water and sequentially dried, first under air overnight thenby high vacuum under P₂O₅, resulting in a colorless powder.

Step 4: Synthesis of2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcids

To a solution of ethyl2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.07 mmol) in THF/MeOH was added 1.5 M LiOH (0.27 mmol). The reactionmixture was stirred at rt for 1 h. Upon completion as detected by LCMS,the solvent was removed by forced air. The residue was taken into DMSOand purified directly via preparative reverse phase using gradientelution (4-100% acetonitrile modified with 0.1% TFA in water modifiedwith 0.1% TFA). The product fractions were directly frozen andlyophilized overnight, yielding an off-white powder.

Example 50

This example describes the synthesis of2-(5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-3-(metasubstituted-phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acids in anembodiment of the invention.

Step 1: Synthesis of Ethyl2-(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates

A solution of ethyl2-(3-(3-bromophenyl)-5-(alkyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.161 mmol, prepared according to the procedure outlined in Example 49,Steps 1-3, using method B in Step 3),tri(tert-butylphosphonium)tetrafluoroborate (0.016 mmol), allylpalladiumchloride dimer (0.008 mmol) and DABCO (0.323 mmol) in dioxane wasbubbled with argon for 5 minutes. Alkylethyne was then added and thereaction mixture was stirred at rt overnight. Upon completion asdetected by LCMS, the reaction mixture was diluted with ethyl acetateand palladium scavenging silica (DMT) was added. After stirring for 2 hat rt the slurry was filtered through a plug of silica. The filtrate wasconcentrated and the residue was purified directly on silica usinggradient elution (20-40% ethyl acetate in hexanes over 20 CV).

Step 2: Synthesis of2-(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcids

The desired compounds were synthesized according to the procedureoutlined in Step 4 of Example 49 providing2-(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids as off-white solids.

Example 51

This example describes the synthesis of4-((1-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide210 in an embodiment of the invention.

Step 1: Synthesis of 7-bromo-4-(tert-butoxy)thieno[3,2-d]pyrimidine

To a partial suspension of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (998mg, 4 mmol) in THF (12 ml) at 0° C. was added KOtBu (4.40 ml, 4.40 mmol)(1M solution in THF). The mixture was stirred at 0° C. for 1.5 h. Themixture was poured into H₂O/NH₄Cl_((aq)) (25 mL/25 mL) and extractedwith EtOAc (50 mL×2). The combined organic layer was dried (Na₂SO₄) andfiltered. After removal of solvent, the product was purified by silicagel chromatography using 5-10% EtOAc/hexane as the eluent to give7-bromo-4-(tert-butoxy)thieno[3,2-d]pyrimidine (350 mg, 1.219 mmol,30.5% yield).

Step 2: Synthesis of4-((1-(4-(tert-butoxy)thieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

In a microwave tube was placedN,N-bis(4-methoxybenzyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(138 mg, 0.25 mmol), 7-bromo-4-(tert-butoxy)thieno[3,2-d]pyrimidine(71.8 mg, 0.250 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine(7.11 mg, 0.050 mmol), CuI (4.76 mg, 0.025 mmol), and Phosphoric acid,potassium salt (159 mg, 0.750 mmol). The air was removed and re-filledwith N₂ (3 times). Then Toluene (Volume: 2 ml) was added and the mixturewas stirred at 110° C. for overnight. After cooling to rt, the mixturewas dilute with EtOAc (3 mL) and filtered through celite and eluted withEtOAc. The filtrate was concentrated and the mixture was purified bysilica gel chromatography using 10-25% EtOAc/hexane as the eluent togive4-((1-(4-(tert-butoxy)thieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide(64 mg, 0.084 mmol, 33.7% yield). MS (M+H)⁺=760.

Step 3: Synthesis of4-((1-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(210)

To a solution of4-((1-(4-(tert-butoxy)thieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide(64 mg, 0.084 mmol) in 1,2-Dichloroethane (1 ml) was add TFA (1 ml,12.98 mmol). The tube was sealed and heated at 100° C. for 30 min undermicrowave irradiation. The mixture was poured into EtOAc/H₂O (30 mL/30mL) and Na₂CO_(3(aq)) was added until the pH of aqueous layer is ca.7.5-8. The organic layer with some suspension was washed with H₂O (20mL×3) and then concentrated to remove all the solvent and trace of H₂O.The product was dried in vacuo for 10 min. Then, to the product wasadded EtOAc (5 mL) and then hexane (50 mL). The solid was filtered andwashed with 5% EtOAc/hexane (3 mL×3) and then dried to give4-((1-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide210 (36.5 mg, 0.079 mmol, 93% yield) as an off white solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.79 (s, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H),7.74-7.68 (m, 2H), 7.68-7.62 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.34 (m,3H), 7.25 (s, 2H), 4.16 (s, 2H); MS (M+H)⁺=464.

Example 52

This example describes the synthesis of4-((1-(4-aminothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide,TFA 211 in an embodiment of the invention.

Step 1: Synthesis of7-bromo-N-(tert-butyl)thieno[3,2-d]pyrimidin-4-amine

To a partial suspension of 7-bromo-4-chlorothieno[3,2-d]pyrimidine(0.998 g, 4 mmol) in EtOH (6 ml) at 80° C. was added2-methylpropan-2-amine (0.585 g, 8.0 mmol) and then Hunig's Base (0.699ml, 4.0 mmol). The mixture was seared and stirred at 80° C. forovernight. The mixture was diluted with CH₂Cl₂ and concentrated toremove all the solvent. The product was dissolved in EtOAc (50 mL) andwashed with H₂O (50 mL). The organic layer was dried (Na₂SO₄) andfiltered. After removal of solvent, the product was purified by silicagel chromatography using 2-5-10% EtOAc/CH₂Cl₂ as the eluent to give7-bromo-N-(tert-butyl)thieno[3,2-d]pyrimidin-4-amine (1.09 g, 3.81 mmol,95% yield).

Step 2: Synthesis of4-((1-(4-aminothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide,TFA (211)

In a microwave tube was placedN,N-bis(4-methoxybenzyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(138 mg, 0.25 mmol),7-bromo-N-(tert-butyl)thieno[3,2-d]pyrimidin-4-amine (71.5 mg, 0.250mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (7.11 mg, 0.050mmol), CuI (4.76 mg, 0.025 mmol), and Phosphoric acid, potassium salt(159 mg, 0.750 mmol). The air was removed and re-filled with N₂ (3times). Then Toluene (2 ml) was added and the mixture was stirred at110° C. for overnight. After cooling to rt, the mixture was dilute withEtOAc (3 mL) and filtered through celite and eluted with EtOAc. Thefiltrate was concentrated and the mixture was purified by silica gelchromatography using 10-25% EtOAc/hexane as the eluent to give4-((1-(4-(tert-butylamino)thieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide.The product was contained some impurity and was subjected for removingthe protection groups directly. The product was dissolved inTFA/dichloroethane (2 mL/1 mL) and was heated at 100° C. for 1 h undermicrowave irradiation. Then, the mixture heated at 120° C. for another1.5 h under microwave irradiation. The mixture was concentrated andsubmit for purification to give4-((1-(4-aminothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide,TFA 211 (5.7 mg, 9.89 μmol, 3.95% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.92 (d, J=4.9 Hz, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H),7.87 (s, 2H), 7.69 (m, 4H), 7.49-7.30 (m, 5H), 7.26 (s, 2H), 4.17 (s,2H); MS (M+H)⁺, 463.

Example 53

This example describes the synthesis of1-methyl-2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)-1H-imidazole-5-carboxylicacid, TFA 212 in an embodiment of the invention.

Step 1: Synthesis of Methyl2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)-1-methyl-1H-imidazole-5-carboxylate

In a microwave tube was placedN,N-bis(4-methoxybenzyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(138 mg, 0.25 mmol), methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate(54.8 mg, 0.25 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine(14.22 mg, 0.100 mmol), CuI (9.52 mg, 0.050 mmol), and Phosphoric acid,potassium salt (159 mg, 0.750 mmol). The air was removed and re-filledwith N₂ (3 times). Then Toluene (2 ml) was added and the mixture wasstirred at 110° C. for overnight. After cooling to rt, the mixture wasdilute with EtOAc (3 mL) and filtered through celite and eluted withEtOAc. The filtrate was concentrated and the mixture was purified bysilica gel chromatography using 10-25% EtOAc/hexane as the eluent togive methyl2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)-1-methyl-1H-imidazole-5-carboxylate(57 mg, 0.082 mmol, 33.0% yield). MS (M+H)+=692.

Step 2: Synthesis of1-methyl-2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)-1H-imidazole-5-carboxylicAcid, TFA (212)

To a solution of methyl2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)-1-methyl-1H-imidazole-5-carboxylate(57 mg, 0.082 mmol) in THF (1 mL) was added LiOH(aq) (1.5 N, 0.4 mL, 0.6mmol). The mixture was stirred at rt for 2 h. Then, 1 N HCl(aq) wasadded slowly until the pH of aqueous layer was about 4-5. The mixturewas extracted with EtOAc (2 mL×10) until no product was detected by UVfrom organic layer. The combined organic layer was dried (Na₂SO₄) andfiltered. After removal of solvent, the product was dried in vacuo togive crude acid intermediate. The intermediate was then dissolved in1,2-dichloroethane/TFA (0.6 mL/0.6 mL) in a microwave tube. The tube wassealed and heat at 100° C. under microwave irradiation for 20 min. Themixture was concentrated and the residue was dissolved in DMF, filter,and submitted for purification to give1-methyl-2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)-1H-imidazole-5-carboxylicacid, TFA 212 (2 mg, 3.63 μmol, 4.40% yield). MS (M+H)⁺=438.

Example 54

This example describes the synthesis of5-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiophene-3-carboxylicacid, TFA 213 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompound was prepared starting fromN,N-bis(4-methoxybenzyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamideand ethyl 5-bromothiophene-3-carboxylate and then hydrolyzed. The finalproduct was purified by reverse phase HPLC chromatography to give5-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiophene-3-carboxylicacid, TFA 213. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 8.45 (s, 1H),7.96 (d, J=1.6 Hz, 1H), 7.73-7.66 (m, 2H), 7.63-7.55 (m, 3H), 7.44-7.32(m, 5H), 7.26 (s, 2H), 4.08 (s, 2H); MS (M+H)⁺=440.

Example 55

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 214 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylateand ethyl2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(63.8 mg, 0.1 mmol) (2 regio-isomers),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(41.6 mg, 0.20 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (8.17 mg, 10.0 μmol),and K₂CO₃ (69.1 mg, 0.50 mmol). The air was removed and re-filled withN₂ (repeat for 3 times). Then, a mixture of 1,4-Dioxane (1.5 ml)/Water(0.5 ml) was added. The mixture was stirred at 95° C. (pre-heated) for1.5 h. After cooling to rt, the mixture was extracted with EtOAc (2mL×3). The combined organic layer was dried (Na₂SO₄) and filtered. Afterremoval of solvent, the product was purified by silica gelchromatography using 40-70% EtOAc/hexane as the eluent to give ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(27 mg, 0.042 mmol, 42.3% yield) and ethyl2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(27 mg, 0.042 mmol, 42.3% yield), total 54 mg.

Step 2: Synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA (214)

To a solution of ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(27 mg, 0.042 mmol) and ethyl2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(27 mg, 0.042 mmol) in THF (1 ml)/MeOH (0.3 ml) was added LiOH(aq) (1.5N, 0.4 mL, 0.6 mmol). The mixture was stirred at 50° C. for 2 h. Aftercooling to rt, 1N HCl_((aq)) was added until the pH of aqueous layer isca. 4. The mixture was concentrated and the residue was dissolved inDMF, filtered through a filter, and submitted for purification to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA (0.9 mg, 1.242 μmol, 2.94% yield) 214 (powder weight: 0.9 mg,tR=5.30 min, final QC) and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA (not collected) (for 214) ¹H NMR (400 MHz, DMSO-d₆) δ 13.15(s, 1H), 8.29 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.78-7.72 (m, 2H), 7.52(dd, J=9.6, 1.8 Hz, 1H), 7.46 (dd, J=8.0, 1.8 Hz, 1H), 7.40 (s, 2H),7.34 (ddd, J=8.5, 5.0, 2.2 Hz, 1H), 7.26 (dd. J=11.0, 8.5 Hz, 1H), 7.12(t, J=7.8 Hz, 1H), 4.10 (s, 2H), 3.85 (s, 3H), 3.15 (d, J=7.0 Hz, 2H),1.14-1.01 (m. 1H), 0.37-0.14 (m, 4H); MS (M+H)⁺=611.

Example 56

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 215 and2-(3-(cyclopropylmethyl)-5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 216 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 215 and2-(3-(cyclopropylmethyl)-5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 216. MS (M+H)⁺=626.

Example 57

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 217 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 218 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 217 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 218. MS (M+H)⁺=611.

Example 58

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 219 and2-(3-(cyclopropylmethyl)-5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 220 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 219 and2-(3-(cyclopropylmethyl)-5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 220. MS (M+H)⁺=626.

Example 59

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 221 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 222 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 221 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 222. MS (M+H)⁺=627.

Example 60

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 223 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 224 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 223 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 224. MS (M+H)⁺=627.

Example 61

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 225 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 226 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 225 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 226. MS (M+H)⁺=627.

Example 62

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 227 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 228 in an embodiment of the invention.

According to similar procedures described above for 212, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 227 and2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 228. MS (M+H)⁺=627; (for 227, HCl salt). ¹H NMR (400 MHz,DMSO-d₆) δ 13.13 (s, 1H), 8.29 (s. 1H), 7.67 (t, J=7.9 Hz, 1H), 7.62(dd, J=7.6, 2.2 Hz, 1H), 7.58 (s, 2H), 7.50 (ddd, J=8.5, 4.8, 2.2 Hz,1H), 7.34 (dd, J=11.3, 8.6 Hz, 1H), 7.19 (dd, J=11.3, 1.6 Hz, 1H), 7.13(dd, J=3.6, 0.9 Hz, 1H), 7.06 (dd, J=8.1, 1.6 Hz, 1H), 6.81 (dt, J=3.6,1.1 Hz, 1H), 4.14 (s, 2H), 3.15 (d, J=6.9 Hz, 2H), 2.44 (d, J=1.1 Hz,3H), 1.19-1.03 (m, 1H), 0.39-0.28 (m, 2H), 0.24-0.14 (m, 2H).

Example 63

This example describes the synthesis of ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate229 in an embodiment of the invention.

In a microwave tube was placed ethyl2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(287 mg, 0.45 mmol) (2 regio-isomers), PdCl₂(dppf)-CH₂Cl₂ adduct (55.1mg, 0.068 mmol), and K₂CO₃ (466 mg, 3.38 mmol). The air was removed andre-filled with N₂ (repeat for 3 times). Then, a solution of4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (252mg, 1.125 mmol) in 1,4-Dioxane (4.5 ml) and Water (1.5 ml) was added.The mixture was stirred at 90° C. (pre-heated) for 1.5 h. After coolingto rt, the mixture was extracted with EtOAc (5 mL×3). The combinedorganic layer was dried (Na₂SO₄) and filtered. After removal of solvent,the product was purified by silica gel chromatography using 25-35%EtOAc/hexane as the eluent to give desired product. The product haslight brown color and can be re-crystallized from CH₂Cl₂/hexane system.Dissolved the product in CH₂Cl₂ (5 mL) and then added hexane (ca. 10mL). Then slowly removed solvent by air blow to ca. ¼ amount of solventand then added hexane (15 mL). The solid was filtered and trituratedwith hexane (3 mL×3) and then dried to give ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate229 (276 mg, 0.422 mmol, 94% yield) as a off-white solid. 241 mg+35 mg,total 276 mg (2 crops). ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (s. 1H),7.81 (t, J=7.8 Hz, 1H), 7.55 (dd, J=7.4, 2.2 Hz, 1H), 7.37 (ddd, J=8.5,4.7, 2.2 Hz, 1H), 7.15-7.04 (m, 3H), 7.00 (dd, J=11.1, 1.6 Hz, 1H), 6.73(dt, J=3.7, 1.0 Hz, 1H), 4.93 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.07 (s,2H), 3.21 (d, J=6.8 Hz, 2H), 2.49 (d, J=1.1 Hz, 3H), 1.41 (t, J=7.1 Hz,3H), 1.19-1.06 (m, 1H), 0.49-0.38 (m, 2H), 0.28 (dt, J=6.1, 4.7 Hz, 2H);MS (M+H)⁺=655.

Example 64

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 230 in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

In a microwave tube was placed ethyl2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(31.9 mg, 0.05 mmol) (2 regio-isomers), PdCl₂(dPPf)-CH₂Cl₂ adduct (8.17mg, 10.0 μmop, and K₂CO₃ (51.8 mg, 0.375 mmol). The air was removed andre-filled with N₂ (repeat for 3 times). Then, a solution of4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (26.0 mg,0.125 mmol) in 1,4-Dioxane (1 ml) and Water (0.5 ml) was added. Themixture was stirred at 90° C. (pre-heated) for 1.5 h. After cooling tort, the mixture was extracted with EtOAc (3 mL×3). The combined organiclayer was dried (Na₂SO₄) and filtered. After removal of solvent, theproduct was purified by silica gel chromatography using 20-40%EtOAc/hexane as the eluent to give ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(30 mg, 0.047 mmol, 94% yield). MS (M+H)⁺=639.

Step 2: Synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid (230)

To a solution of ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(30 mg, 0.047 mmol) in THF (1 ml)/MeOH (0.3 ml) was added LiOH(aq) (1.5N, 0.4 mL, 0.6 mmol). The mixture was stirred at 50° C. for 1 h. Aftercooling to rt, 1N HCl_((aq)) was added until the pH of aqueous layer isca. 3-4. The mixture was poured into EtOAc/H₂O (5 mL/5 mL). The aqueouslayer was extracted with EtOAc (5 mL×3). The combined organic layer wasdried (Na₂SO₄) and filtered. After removal of solvent, the product wasdissolved in CH₂Cl₂ (2 mL) and then added hexane (40 mL). The resultedsolid was filtered and triturated with hexane (3 mL×3) and then driedunder house vacum at 50° C. for overnight to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 230 (22 mg, 0.036 mmol, 77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ13.10 (s, 1H), 8.29 (s, 1H), 7.76 (dd, J=7.4, 2.3 Hz, 1H), 7.67 (t,J=7.9 Hz, 1H), 7.57 (s, 2H), 7.54 (ddd, J=8.6, 4.8, 2.3 Hz, 1H), 7.33(dd, J=11.2, 8.6 Hz, 1H), 7.20 (dd, J=11.3, 1.6 Hz, 1H), 7.07 (dd,J=8.1, 1.6 Hz, 1H), 6.70 (t, J=3.5 Hz, 1H), 6.22 (dt, J=3.1, 1.0 Hz,1H), 4.15 (s, 2H), 3.15 (d, J=6.9 Hz, 2H), 2.27 (s, 3H), 1.17-1.06 (m,1H), 0.38-0.28 (m, 2H), 0.24-0.14 (in, 2H); MS (M+H)⁺=611.

Example 65

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiazol-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 231 in an embodiment of the invention.

According to similar procedures described above for 230, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiazol-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 231. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 8.30 (dd,J=7.2, 2.3 Hz, 1H), 8.28 (s, 1H), 7.70-7.59 (m, 3H), 7.54 (s, 2H), 7.43(dd, J=11.1, 8.7 Hz, 1H), 7.16 (dd, J=11.4, 1.6 Hz, 1H), 7.05 (dd,J=8.1, 1.6 Hz, 1H), 4.14 (s, 2H), 3.19-3.14 (m, 2H), 2.49 (d, J=1.2 Hz,3H), 1.18-1.05 (m, 1H), 0.39-0.29 (m, 2H), 0.24-0.15 (m, 2H); MS(M+H)⁺=628.

Example 66

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(2-methylthiazol-5-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 232 in an embodiment of the invention.

According to similar procedures described above for 230, the titlecompounds were prepared to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(2-methylthiazol-5-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 232. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.97(s, 1H), 7.68 (dd, J=7.4, 2.0 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.57 (m,3H), 7.39 (dd, J=10.8, 8.7 Hz, 1H), 7.17 (d, J=11.3 Hz, 1H), 7.05 (d,J=8.3 Hz, 1H), 4.15 (s, 2H), 3.16 (d, J=6.9 Hz, 2H), 2.66 (s, 3H),1.18-1.01 (m, 1H), 0.37-0.27 (m, 2H), 0.21 (d, J=4.9 Hz, 2H); MS(M+H)⁺=628.

Example 67

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 233 in an embodiment of the invention.

According to similar procedures described above for 230, the titlecompounds were prepared to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 233. ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (s, 1H), 8.29 (s, 1H), 7.63(dd, J=7.5, 2.2 Hz, 1H), 7.56 (dd, J=9.6, 1.8 Hz, 1H), 7.53-7.49 (m,1H), 7.49-7.44 (m, 1H), 7.42 (s, 2H), 7.34 (dd, J=11.3, 8.6 Hz, 1H),7.19-7.11 (m, 2H), 6.81 (dt, J=3.6, 1.1 Hz, 1H), 4.08 (s, 2H), 3.16 (d,J=6.9 Hz, 2H), 2.44 (d, J=1.1 Hz, 3H), 1.17-1.02 (m, 1H), 0.35-0.27 (m,2H), 0.22-0.14 (m, 2H); MS (M+H)⁺=627.

Example 68

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(thiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 234 in an embodiment of the invention.

According to similar procedures described above for 230, the titlecompounds were prepared and the final product was purified by reversephase HPLC chromatography to give2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(thiophen-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 234. MS (M+H)⁺=613.

Example 692-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 451

Step 1. Synthesis of Ethyl 3-(naphthalen-1-yl)-3-oxopropanoate

Lithium hexamethyldisiloxane (LHMDS) (1 M in hexane, 7.8 mL, 7.8 mmol)was dissolved in dry THF (5 mL) and cooled down at −78° C. Ethyl acetate(760 pt, 7.8 mmol) was added dropwise and the reaction mixture wasstirred for 30 min at −78° C. 1-Napthoyl chloride (1 mL, 5.2 mmol) wasdissolved in dry THF (5 mL) and was cooled down at −78° C. To thissolution, the ethyl acetate/LHMDS solution was added dropwise and thereaction mixture was warmed to ambient temperature over 2 h. Reactionwas quenched with ammonium chloride, diluted with ethyl acetate (50 mL).The organic layer was separated and washed with water (50 mL), brine (50mL) and dried with anhydrous magnesium sulfate. The residue was purifiedby flash chromatography (Combi-flash Rf, hexane ethyl/acetate=5%isocratic) to give ethyl 3-(naphthalen-1-yl)-3-oxopropanoate (300 mg,24%).

Step 2. Synthesis of Ethyl3-(naphthalen-1-yl)-3-oxo-2-(4-sulfamoylbenzyl)propanoate

Ethyl 3-(naphthalen-1-yl)-3-oxopropanoate (300 mg, 1.24 mmol) wasdissolve in dry 1,4-dioxane (2 mL) and sodium hydride (70 mg, 1.74 mmol)was added. The reaction mixture was stirred at room temperature for 30min and 4-(bromomethyl)benzenesulfonamide (372 mg, 1.48 mmol) was added.The reaction mixture was stirred overnight at room temperature. Theresidue was purified by flash chromatography (Combi-flash Rf,hexane/methanol, 0-60% gradient) to give ethyl3-(naphthalen-1-yl)-3-oxo-2-(4-sulfamoylbenzyl)propanoate (380 mg, 75%).

Step 3. Synthesis of Ethyl2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

Ethyl 3-(naphthalen-1-yl)-3-oxo-2-(4-sulfamoylbenzyl)propanoate (260 mg,0.63 mmol), tert-butyl 2-hydrazinylthiazole-4-carboxylate (137 mg, 0.63mmol), p-toluene sulfonic acid (120 mg, 0.63 mmol) and ethanol (6 mL)were placed in microwave vial and irradiated at 110° C. for 3 h. Thereaction mixture was diluted with ethyl acetate (50 mL) and washed withsaturated sodium bicarbonate (20 mL), brine (50 mL) and cried withanhydrous magnesium sulfate. The residue was purified by flashchromatography (Combi-flash Rf, DCM/methanol, 0-10% gradient) to giveethyl2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(210 mg, 60%).

Step 4.2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 451

Ethyl2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(50 mg, 0.096 mmol) was dissolved in THF/MeOH (1 mL:1 mL) and LiOH (5 M,500 μL) was added. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was neutralized by addition ofhydrochloric acid (1.2 M), diluted with ethyl acetate (15 mL), washedwith water (10 mL) and dried with anhydrous magnesium sulfate. Theorganic layer was concentrated down using rotary evaporator anddissolved in a mixture of DMSO and MEOH and purified by HPLC (PhenomenexGemini C18, H₂O/CH₃CN gradient from 20% to 85% CH₃CN for 4 min, 0.1%TFA) to give the title compound 451 (76%). ¹H-NMR (d⁶-DMSO) δ 8.19 (s,1H), 8.09 (d, 2H, J=1.6 Hz), 8.00 (d, 1H, J=8 Hz), 7.86 (d, 1H, J=8 Hz)7.63-7.51 (m, 6H), 7.12 (d, 1H, J=8 Hz), 3.69 (s, 2H); MS (ES) 506.9(M+H)⁺ LCMS RT=0.88 min.

Example 702-(3-(3,4-difluorophenyl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 452

Using procedures analogous to that described for the preparation of 451,the title compounds were prepared and purified by HPLC:2-(3-(3,4-difluorophenyl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 452 ¹H-NMR (d⁶-DMSO) δ 8.18 (s, 1H), 7.85 (d, 2H, J=8.4 Hz), 7.56(m, 1H), 7.45-7.41 (m, 4H), 3.99 (s, 2H); MS (ES) 492.9 (M+H)⁺ LCMSRT=0.88 min.

Example 712-(5-hydroxy-3-(pyridin-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 453

Using procedures analogous to that described for the preparation of 451,the title compounds were prepared and purified by HPLC:2-(5-hydroxy-3-(pyridin-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 453. MS (ES) 457.9 (M+H)+ LCMS RT=0.30 min.

Example 722-(3-(6-fluoronaphthalen-1-yl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 454

Using procedures analogous to that described for the preparation of 451,the title compounds were prepared and purified by HPLC:2-(3-(6-fluoronaphthalen-1-yl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 454. ¹H-NMR (d⁶-DMSO) δ 8.20 (m, 2H), 7.88 (d, 2H, J=8 Hz),7.70-7.55 (m. 5H), 7.32 (m, 1H), 7.12 (d, 1H, J=8 Hz), 3.69 (s, 2H); MS(ES) 524.9 (M+H)⁺ LCMS RT=0.94 min.

Example 732-(3-(3,4-difluorophenyl)-5-methoxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 455

2-(3-(3,4-Difluorophenyl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 452 (20 mg, 0.038 mmol) was dissolved in anhydrous DMF (300 μL).Anhydrous potassium carbonate (16 mg, 0.114 mmol) and methyl iodide (3μL, 0.05 mmol) were added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate (5 mL) and washed with water (3×1 mL). The organic layers wereconcentrated by rotary evaporator and THF (500 μL) and sodium hydroxide(5 N, 200 μL) were added. After 1 h, the reaction mixture wasneutralized with hydrochloric acid (0.1 M) and the residue was purifiedby HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 20% to 95% CH₃CNfor 4 min, 0.1% TFA) to give the title compound 455 (85%). ¹H-NMR(d⁶-DMSO) δ 8.20 (s, 1H), 7.81 (d, 2H, J=8 Hz), 7.54-7.50 (m, 2H),7.39-7.36 (m, 3H), 3.69 (s, 2H), 3.49 (s, 3H); MS (ES) 506.9 (M+H)⁺ LCMSRT=0.89 min.

Example 742-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 459

Step 1. Synthesis of 3-(3-methoxyphenyl)-3-oxopropanal

3-Methoxyphenyl acetophenone (3 g, 0.17 mol) was dissolved in anhydrousTHF (25 mL) and cooled to 0° C. Sodium hydride (930 mg, 0.23 mol) andethyl formate (4.3 mL, 0.53 mol) were added. The reaction mixture wasstirred overnight at room temperature, quenched with sodium hydroxide (2N), and washed with diethyl ether. The water layers were acidified withhydrochloric acid (2 N) and extracted with diethyl ether (3×50 mL). Theorganic layers were dried with anhydrous magnesium sulfate andconcentrated down with rotary evaporator to give3-(3-methoxyphenyl)-3-oxopropanal (quantitative yield) which wassufficiently pure to be used in subsequent reaction.

Step 2. Synthesis of 3-(3-methoxyphenyl)-1H-pyrazole

To a stirred solution of 3-(3-methoxyphenyl)-3-oxopropanal in ethanol,hydrazine (1 mL, 0.3 mmol) was added and the reaction mixture wasrefluxed for 3 h. The reaction mixture was concentrated to half of itsoriginal volume, water (50 mL) and sodium hydroxide (1 M, 100 mL) wereadded. The mixture was extracted with ethyl acetate (3×50 mL) and driedwith anhydrous magnesium sulfate. The organic layers were filtered offand concentrated by rotary evaporator to give a yellow liquid (3 g,92%). The product was sufficiently pure for the subsequent reaction.

Step 3. Synthesis of 4-bromo-3-(3-methoxyphenyl)-1H-pyrazole

3-(3-Methoxyphenyl)-1H-pyrazole (3 g, 0.017 mol) was dissolved inanhydrous DMF (30 mL) and cooled to 0° C. NBS (3.20 g, 0.018 mol) wasadded in three portions and the reaction mixture was stirred at roomtemperature for overnight. The reaction mixture was poured into amixture of ethyl acetate and saturated sodium bicarbonate (1:1, 300 mL)and organic layer was separated, washed with brine (2×100 mL) and driedwith anhydrous magnesium sulfate. The solvents were removed by rotaryevaporator and purified by flash chromatography (Combi-flash Rf,hexane/ethyl acetate, 0-50% gradient) to give4-bromo-3-(3-methoxyphenyl)-1H-pyrazole (3 g, 70%).

Step 4. Synthesis of Ethyl2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

4-Bromo-3-(3-methoxyphenyl)-1H-pyrazole (3 g, 0.012 mol) was dissolvedin anhydrous DMSO (15 mL) and anhydrous potassium carbonate (2.46 g,0.018 mol) and ethyl 2-bromothiazole-4-carboxylate (2.8 g, 0.012) wereadded. The reaction mixture was heated at 120° C. for 6 h. After coolingdown, the reaction mixture was poured into water and the precipitate wasfiltered off to give ethyl2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(3.54 g, 73%).

Step 4A. Synthesis of Ethyl2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid

Ethyl2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (3g, 0.008 mol) was dissolved in anhydrous DCM (20 mL). Boron tribromide(1 M in DCM, 9.5 mL, 0.0096 mol) was added dropwise. The reactionmixture was stirred at room temperature for 30 min. The precipitate wasfiltered off and washed with DCM to give ethyl2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (2 g, 60%).

Step 4B. Synthesis of Isopropyl2-(4-bromo-3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

Ethyl2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (500 mg, 0.1 mmol) was dissolved in anhydrous DMF. Potassiumcarbonate (2.1 g, 15 mmol) and isopropyl bromide (1.4 mL, 10 mmol) wereadded and the reaction was irradiated at 130° C. for 40 min in amicrowave reactor. The reaction mixture was poured into water andextracted with ethyl acetate (3×40 mL). The organic layers were washedwith brine (2×50 mL) and dried with anhydrous magnesium sulfate. Thesolvents were removed by rotary evaporator and purified by purified byflash chromatography (Combi-flash Rf, hexane/ethyl acetate, 0-20%gradient) to give isopropyl2-(4-bromo-3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(520 mg, 84%).

Step 5. Synthesis of Isopropyl2-(3-(3-isopropoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

Isopropyl2-(4-bromo-3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(520 mg, 1.15 mmol) was dissolved in anhydrous THF (5 mL) and potassiumacetate (340 mg, 3.46 mmol), PdCl₂(dppf) (0.9 mg, 0.0011 mmol) andbis(pinacolato)diborane (408 mg, 1.61 mmol) were added. The vial waspurged with argon for 5 min. The reaction was heated at 100° C. for 2 h.The reaction mixture was diluted with ethyl acetate and filtered througha plug of celite. The solvent was removed by rotary evaporator andpurified by flash chromatography (Combi-flash Rf, hexane/ethyl acetate,0-40% gradient) to give a mixture of isopropyl2-(3-(3-isopropoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylateand isopropyl2-(3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate.

Step 6. Synthesis of Isopropyl2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

A mixture of isopropyl2-(3-(3-isopropoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylateand 2-(3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(500 mg, 1 mmol), potassium carbonate (414 mg, 3 mmol), Pd(PPh₃)₄ (1.2mg, 0.001 mmol), and 4-(bromomethyl)benzenesulfonamide (275 mg, 1.1mmol) were added to a microwave vial, followed by THF (8 mL) and water(3 mL). The vial was sealed and heated at 100° C. for 1 h. The reactionmixture was cooled, poured into water, and extracted with ethyl acetate(3×20 mL). The organic layers were washed with brine (2×20 mL) and driedwith anhydrous magnesium sulfate. The solvents were removed by rotaryevaporator and purified by purified by flash chromatography (Combi-flashRf, hexane/ethyl acetate, 0-70% gradient) to give the title compound(150 mg, 27%).

Step 7. Synthesis of2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 459

Isopropyl2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(50 mg, 0.09 mmol) was dissolved in THF/MeOH (1 mL: 1 mL) and LiOH (5 M,500 μL) was added. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was neutralized by addition ofhydrochloric acid (1.2 M), diluted with ethyl acetate (15 mL), washedwith water (10 mL), and dried with anhydrous magnesium sulfate. Theorganic layer was concentrated using a rotary evaporator, dissolved in amixture of DMSO and MEOH, and purified by HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 45% to 85% CH₃CN for 7 min, 0.1% TFA) to givethe title compound 459 (34 mg, 76%). ¹H-NMR (d⁶-DMSO) δ 8.24 (m, 2H),7.78 (d, 2H, J=8 Hz), 7.44 (d, 2H, J=8 Hz), 7.39-7.30 (m, 3H), 7.22 (d,1H, J=8 Hz), 7.09 (d, 1H, J=4 Hz), 6.99-6.96 (m, 1H), 4.51 (m, 1H), 4.15(s, 2H), 1.27 (d, 6H, J=8 Hz); MS (ES) 499.0 (M+H)⁺ LCMS RT=1.07 min.

Example 752-(3-(3-(cyclopentyloxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 460

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(3-(cyclopentyloxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 460 ¹H-NMR (d⁶-DMSO) δ 8.55 (m, 2H), 8.25 (d, 2H, J=4 Hz), 7.77 (d,2H, J=4 Hz), 7.55-7.26 (m, 3H), 7.22 (d, 1H, J=8 Hz), 7.09 (d, 1H, J=8Hz), 6.99-6.96 (m, 1H), 4.74 (m, 1H), 4.15 (s, 2H), 1.91-1.82 (m, 2H),1.69-1.58 (m, 4H), 1.23 (m, 2H); MS (ES) 525.0 (M+H)⁺ LCMS RT=1.15 min.

Example 762-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-3-yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 461

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-3-yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 461 MS (ES) 540.7 (M+H)⁺ LCMS RT=1.13 min.

Example 772-(3-(3-((3-methoxybenzyl)oxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 462

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(3-((3-methoxybenzyl)oxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 462 MS (ES) 576.9 (M+H)⁺ LCMS RT=1.02 min.

Example 782-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 463

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 463. MS (ES) 540.9 (M+H)⁺ LCMS RT=0.76 min.

Example 792-(3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 464

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 464 MS (ES) 532.9 (M+H)⁺ LCMS RT=0.98 min.

Example 802-(3-(3-(pyridin-3-ylmethoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 465

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(3-(pyridin-3-ylmethoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 465 MS (ES) 548.0 (M+H)⁺ LCMS RT=0.68 min.

Example 812-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid, TFA 466

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid, TFA 466 MS (ES) 547.9 (M+H)⁺ LCMS RT=0.68 min.

Example 822-(5-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 474

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(5-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 474 ¹H-NMR (d⁶-DMSO) δ 8.24 (s, 1H), 8.13 (s, 1H), 7.91-8.03 (m,4H), 7.80 (d, J=8.2 Hz, 2H), 7.52-7.58 (m, 3H), 7.32 (s, 2H), 4.25 (s,2H); MS (ES) 491 (M+H)⁺ LCMS RT 1.04 min.

Example 832-(5-(pyridin-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 475

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(5-(pyridin-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 475 MS (ES) 442 (M+H)⁺ LCMS RT 0.64 min.

Example 842-(3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 476

Using procedures analogous to that described for the preparation of 459,the title compound was prepared and purified by HPLC:2-(3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 476. ¹H-NMR (d⁶-DMSO) δ 8.27 (d, J=9.24 Hz, 2H), 7.76-7.78 (m, 4H),7.29-7.46 (m, 8H), 4.2 (s, 2H), 2.35 (s, 3H); MS (ES) 549 (M+H)⁺ LCMS RT1.27 min.

Example 852-(3-(6-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 456

Route B-A

Using procedures analogous to those described in the preparation of 459,Step 1-2, 3-(3-bromo-4-fluorophenyl)-1H-pyrazole was prepared.

Step 2A: 3-(3-bromo-4-fluorophenyl)-1H-pyrazole (100 mg, 0.415 mmol),3-methoxyphenyl boronic acid (95 mg, 0.622 mmol), K₂CO₃ (678 mg, 4.977mmol), and a 2:1 mixture of dioxane/H₂O (8.0 mL) were combined in amicrowave vial and then degassed and purged with argon (3×). Pd(dppf)Cl₂was added and the reaction mixture was heated to 120° C. for 1 h. Thereaction mixture was cooled to room temperature. NaOH (8 mL, 1M) wasadded and the mixture was extracted with EtOAc (3×50 mL). The combinedorganic layers were then washed with brine, dried over MgSO₄, filtered,and concentrated by rotary evaporator. The crude product was purified byflash chromatography (Combi-flash Rf, dichloromethane/methanol, 0-10%gradient) to give 3-[4-fluoro-3-(3-methoxyphenyl)phenyl]-1H-pyrazole(419 mg, 94%). ¹H-NMR (CDCl₃) δ 7.69 (1H, d, J=2.2 Hz), 7.71 (1H, m),7.63 (1H, d, J=2.2 Hz), 7.37 (1H, t, J=8.0 Hz), 7.21-7.09 (3H, m), 6.78(1H, dd, J=8.2, 2.3 Hz), 6.61 (1H, d, J=2.3 Hz), 3.84 (3H, s). MS(M+H)⁺=270.1.

Using procedures analogous to those described in the preparation of 459,Steps 3-7, the title compound was prepared was prepared and purified byHPLC:2-(3-(6-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 456 MS (ES) 565.0 (M+H)⁺ LCMS RT=1.08 min.

Example 862-(3-(3′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 457

Using procedures analogous to those described in the preparation of 456,the title compound was prepared was prepared and purified by HPLC:2-(3-(3′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 457 MS (ES) 568.9 (M+H)⁺ LCMS RT=1.16 min.

Example 872-(3-(3′,6-difluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 458

Using procedures analogous to those described in the preparation of 456,the title compound was prepared was prepared and purified by HPLC:2-(3-(3′,6-difluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 458 MS (ES) 552.9 (M+H)⁺ LCMS RT=1.12 min.

Example 882-(3-(4-methyl-3-(pyridin-3-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 486

Using procedures analogous to those described in the preparation of 459,Steps 1-6,2-(3-(3-chloro-4-methylphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid was prepared.

Modified Step 7: A flame dried flask was charged withbis(tri-tert-butylphosphine)palladium (5.1 mg, 10 mol %), cesiumcarbonate (1 mL, 1 M solution), pyridin-3-ylboronic acid (25 mg, 0.2mmol),2-(3-(3-chloro-4-methylphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (51 mg, 0.1 mmol), and THF (2 mL). The reaction mixture wasmicrowave irradiated at 120° C. for 20 min and the solvent was removedby rotary evaporator. The residue was filtered through celite pad withMeOH, then solvent was removed by rotary evaporator. The residue waspurified by HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 25% to85% CH₃CN for 4 min, 0.1% TFA) to give the title compound 486 (32 mg,60%). ¹H-NMR (MeOD) δ 8.77 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.25 (d,J=8.0 Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J=7.6, 5.6 Hz, 1H), 7.81 (d,J=8.4 Hz, 2H), 7.74 (dd, J=7.6, 1.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H),7.39 (d, J=8.0 Hz, 2H), 4.21 (s, 2H), 2.34 (s, 3H); MS (ES) 532.7(M+H)⁺, LCMS RT=0.82 min.

Example 892-(3-(3′-amino-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 487

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′-amino-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 487 ¹H-NMR (MeOD) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.81 (d, J=8.4 Hz,2H), 7.63 (dd, J=7.6, 6.6 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.42 (d,J=1.6 Hz, 1H), 7.40 (s, 2H), 7.38 (s, 1H), 7.27-7.20 (m, 2H), 7.15 (s,1H), 4.19 (s, 2H), 2.30 (s, 3H); MS (ES) 546.7 (M+H)⁺; LCMS RT=0.87 min.

Example 902-(3-(3′-ethyl-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 488

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′-ethyl-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 488 ¹H-NMR (MeOD) δ 8.34 (s, 1H), 8.13 (s, 1H), 7.83 (d, J=8.4 Hz,2H), 7.59 (dd, J=8.0, 2.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.41 (d,J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.15 (s,1H), 7.10 (d, J=8.0 Hz, 1H), 4.20 (s, 2H), 2.73 (q, J=8.0 Hz, 2H), 2.29(s, 3H), 1.30 (t, J=8.0 Hz, 3H); MS (ES) 559.4 (M+H)⁺; LCMS RT=1.28 min.

Example 912-(3-(3′,5′-difluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 489

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′,5′-difluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 489; MS (ES) 569.6 (M+H)⁺; LCMS RT=1.24 min.

Example 922-(3-(4-methyl-3-(pyridin-4-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 490

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(4-methyl-3-(pyridin-4-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 490; ¹H-NMR (MeOD) δ 8.80 (br s, 2H), 8.44 (s, 1H), 8.17 (s, 1H),7.85-7.76 (m, 5H), 7.49 (d, J=6.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.40(s, 1H), 7.38 (s, 1H), 4.21 (s, 2H), 2.39 (s, 3H); MS (ES) 533.6 (M+H)⁺;LCMS RT=0.83 min.

Example 932-(3-(6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 491

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 491 ¹H-NMR (MeOD) δ 8.34 (s, 1H), 8.14 (s, 1H), 7.89-7.82 (m, 2H),7.83 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.0 Hz,2H), 7.49-7.35 (m, 4H), 7.29 (d, J=8.0 Hz, 2H), 4.20 (s, 2H), 2.30 (s,H); MS (ES) 531.6 (M+H)⁺; LCMS RT=1.18 min.

Example 942-(3-(3′,4′-difluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 492

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′,4′-difluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 492 MS (ES) 567.9 (M+H)⁺; LCMS RT=1.20 min.

Example 952-(3-(4′-fluoro-3′,6-dimethyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 493

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(4′-fluoro-3′,6-dimethyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 493 MS (ES) 563.9 (M+H)⁺; LCMS RT=1.25 min.

Example 962-(3-(3′-fluoro-4′-methoxy-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 494

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′-fluoro-4′-methoxy-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 494 MS (ES) 579.6 (M+H)⁺; LCMS RT=1.18 min.

Example 972-(4-(4-sulfamoylbenzyl)-3-(3′,5′,6-trimethyl-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 495

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(4-(4-sulfamoylbenzyl)-3-(3′,5′,6-trimethyl-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 495 MS (ES) 559.9 (M+H)⁺; LCMS RT=1.29 min.

Example 982-(3-(3′-cyano-4′,6-dimethyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 496

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′-fluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 496 MS (ES) 549.6 (M+H)⁺; LCMS RT=1.18 min.

Example 992-(3-(3′-fluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 497

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(3′-fluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 497 MS (ES) 549.6 (M+H)⁺; LCMS RT=1.18 min.

Example 1002-(3-(4′-fluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 498(Compound VV)

Using procedures analogous to those described in the preparation of 486,the title compound was prepared and purified by HPLC:2-(3-(4′-fluoro-6-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 498 MS (ES) 549.6 (M+H)⁺; LCMS RT=1.16 min.

Example 1012-(3-(3′-ethyl-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 513

Using procedures analogous to those described in the preparation of 459,Steps 1-6,2-(3-(3-chloro-4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid was prepared.

Modified Step 7: To2-(3-(3-chloro-4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (50 mg, 0.10 mmol) in dioxane/water (2.5 mL, 4:1) was added3-ethylphenyl)boronic acid (23 mg, 0.15 mmol), followed by Cs₂CO₃ (68mg, 0.20 mmol), Pd₂(dba)₃ (10.0 mg, 0.01 mmol), and t-Bu₃P (5 μL, 0.03mmol). This solution was capped and purged with argon. The reactionmixture was heated at 95° C. for 24 h. The reaction mixture was cooleddown and diluted with HCl (10 mL, 1M) and extracted with ethyl acetate(3×15 mL). The combined organic layers were then dried with MgSO4 andconcentrated by rotary evaporator. The crude product was then purifiedby HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 25% to 85% CH₃CNfor 4 min, 0.1% TFA) to give2-(3-(3′-ethyl-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 513 (12 mg, 21%). ¹H-NMR (MeOD) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.86(d, J=8.24 Hz, 2H), 7.77 (d, J=6.4 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.33(t, J=9.62 Hz, 1H), 7.16 (d, J=7.79 Hz, 2H), 7.03 (m, 1H), 4.23 (s, 2H),3.63 (q, J=7.1, 14.2 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H); MS (ES) 562.9(M+H)⁺; LCMS RT=1.24 min.

Example 1022-(3-(3′-ethyl-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 514

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3′-ethyl-6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 514 ¹H-NMR (MeOD) δ 8.36 (s, 1H), 8.16 (s, 1H), 7.87 (d, J=6.4 Hz,2H), 7.81 (m, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.46 (M, 2H), 7.34 (m, 2H),4.24 (s, 2H); MS (ES) 602.9 (M+H)⁺; LCMS RT=1.30 min.

Example 1032-(3-(6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 515

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(6-fluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 515 MS (ES) 544.0 (M+H)⁺; LCMS RT=1.18 min.

Example 1042-(3-(6-fluoro-3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 516

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(6-fluoro-3′,4′-dimethyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 516 MS (ES) 562.9 (M+H)⁺; LCMS RT=1.23 min.

Example 1052-(4-(4-sulfamoylbenzyl)-3-(3′,4′,6-trifluoro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 517

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(4-(4-sulfamoylbenzyl)-3-(3′,4′,6-trifluoro-[1,1′-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 517 MS (ES) 571.0 (M+H)⁺; LCMS RT=1.18 min.

Example 1062-(3-(4′,6-difluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 518

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(4′,6-difluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 518 MS (ES) 582.9 (M+H)⁺; LCMS RT=1.14 min.

Example 1072-(3-(3′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 519

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 519 MS (ES) 530.9 (M+H)⁺; LCMS RT=1.00 min.

Example 1082-(3-(3′,6-difluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 520

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3′,6-difluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 520 MS (ES) 566.9 (M+H)⁺; LCMS RT=1.22 min.

Example 1092-(3-(3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 521

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 521 MS (ES) 546.9 (M+H)⁺; LCMS RT=0.89 min.

Example 1102-(3-(3-(pyridin-3-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 522

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3-(pyridin-3-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 522 MS (ES) 517.9 (M+H)⁺; LCMS RT=0.82 min.

Example 1112-(3-(3′-amino-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 523

Using procedures analogous to those described in the preparation of 513,the title compound was prepared and purified by HPLC:2-(3-(3′-amino-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 524 MS (ES) 532.0 (M+H)⁺; LCMS RT=0.70 min.

Example 1122-(5-cyclopropyl-3-(4′,6-difluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 482

Route C

Step 1. Synthesis of1-(3-chloro-4-fluorophenyl)-3-cyclopropylpropane-1,3-dione

1-(3-Chloro-4-fluorophenyl)ethan-1-one (1.5 g, 8.72 mmol, 1 eq) wasdissolved in THF and cooled to −78° C. After 10 minutes of stirring,LHMDS (1 M in hexanes, 12.2 mL, 1.4 eq) was added dropwise over 20minutes. This was allowed to stir for an additional 20 minutes thencyclopropanecarbonyl chloride (1.1 mL, 12.2 mmol, 1.4 eq) was addeddropwise. The reaction was allowed to stir for 3 h at which time it wasbrought to room temperature. Reaction was quenched with 1 M HCl andextracted with ethyl acetate. The aqueous layer was back extracted threetimes with ethyl acetate. The organic layer was washed with brine anddried over MgSO₄. The reaction mixture was purified by flashchromatography (Combi-flash Rf, hexane/ethyl acetate, 0-20% gradient) togive 1-(3-chloro-4-fluorophenyl)-3-cyclopropylpropane-1,3-dione (1 g,50%). MS (ES) 241 (M+H)⁺; LCMS RT 1.357 min.

Step 2. Synthesis of4-(2-(3-chloro-4-fluorobenzoyl)-3-cyclopropyl-3-oxopropyl)benzenesulfonamide

1-(3-Chloro-4-fluorophenyl)-3-cyclopropylpropane-1,3-dione (1 g, 4.16mmol, 1 eq) was dissolved in DMSO (10 mL) and stirred.4-(bromomethyl)benzenesulfonamide (1.34 g, 5.4 mmol, 1.3 eq), Cs₂CO₃(1.75 g, 5.4 mmol, 1.3 eq), and sodium iodide (624 mg, 4.16 mmol, 1 eq)were added. The reaction was stirred at 50° C. for 1 hour. After thistime, the reaction was poured into 1 M HCl and extracted with ethylacetate. The aqueous layer was back extracted three times with ethylacetate. The combined organics were washed with brine and dried overMgSO₄. The reaction was purified by flash chromatography (Combi-flashRf, hexane/ethyl acetate, 0-80% gradient) to give4-(2-(3-chloro-4-fluorobenzoyl)-3-cyclopropyl-3-oxopropyl)benzenesulfonamide(750 mg, 45%). MS: (ES) 410 (M+H)⁺; LCMS RT 1.14 min.

Step 3. Synthesis of ethyl2-(3-(3-chloro-4-fluorophenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

4-(2-(3-Chloro-4-fluorobenzoyl)-3-cyclopropyl-3-oxopropyl)benzenesulfonamide(700 mg, 1.7 mmol, 1 eq) was added to a microwave vial with ethyl2-hydrazinylthiazole-4-carboxylate (300 mg, 1.7 mmol, 1 eq) andp-toluenesulfonic acid (650 mg, 3.4 mmol, 2 eq). The reactants werepurged with argon gas then dissolved with ethanol (4 mL). The reactionwas run in the microwave reactor for 15 minutes at 100° C. The reactionwas purified by flash chromatography (Combi-flash Rf, hexane/ethylacetate=0-80% gradient) to give ethyl2-(3-(3-chloro-4-fluorophenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(300 mg).

Step 4.2-(5-cyclopropyl-3-(4′,6-difluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 482

Ethyl2-(3-(3-chloro-4-fluorophenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(15 mg, 0.03 mmol) was placed into a microwave vial along with(4-fluorophenyl)boronic acid (8 mg, 0.06 mmol, 2 eq) and thePd(P(t-Bu)₃)₂ (5 mg). The reaction mixture was purged with vacuum andargon gas. Following this, Cs₂CO₃ (1 M, 1 mL) and THF (2 mL) were added.The reaction was heated in the microwave for 15 minutes at 100° C. AfterLC/MS showed complete conversion to product along with hydrolysis of theester, solvent was removed by rotary evaporation and the reaction waspurified by HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 45% to85% CH₃CN for 7 min, 0.1% TFA) to give the title compound 482 (5 mg).¹H-NMR (MeOD): δ 8.27 (s, 1H) 7.85 (d, J=12 Hz, 2H), 7.57-7.63 (m, 1H),7.5 (d, J=16 Hz, 1H), 7.29-7.42 (m, 4H), 7.12-7.25 (m, 4H), 4.25 (s,2H), 2.32-2.41 (m, 1H), 1.15 (d, J=12 Hz, 2H), 0.7 (d, J=9 Hz, 2H); (ES)593 (M+H)⁺ LCMS RT=1.28 min.

Example 1132-(5-cyclopropyl-3-(6-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 483

Using procedures analogous to those described in the preparation of 482,the title compound was prepared and purified by HPLC:2-(5-cyclopropyl-3-(6-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 483 ¹H-NMR (CDCl₃) δ 8.13 (s, 1H), 7.85 (d, J=8 Hz, 2H), 7.55-7.59(m, 1H), 7.35-7.39 (m, 2H), 7.25-7.31 (m, 4H), 7.17 (t, J=18.84 Hz, 1H),7.04 (d, J=7.56 Hz, 1H), 6.91-6.94 (dd, J=2, 2 Hz, 1H), 6.73 (s, 1H),5.04 (s, Broad, 2H), 4.17 (s, 2H), 3.87 (s, 3H), 2.23-2.27 (m, 1H), 1.12(d, J=7 Hz. 2H), 0.73 (d, J=5 Hz, 2H), MS (ES) 605 (M+H)⁺ LCMS RT=1.25min.

Example 1142-(5-cyclopropyl-3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 484

Using procedures analogous to those described in the preparation of 482,the title compound was prepared and purified by HPLC:2-(5-cyclopropyl-3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 484′H-NMR (CDCl₃) δ 8.10 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.5 (dd,J₁=2; J₂=2 Hz, 1H), 7.41-7.45 (m, 1H), 7.22-7.32 (m, 7H), 7.13 (t, J=19Hz, 1H), 5.06 (s, 2H), 4.14 (s, 2H), 2.40 (s, 3H), 2.17-2.23 (m, 1H),1.07 (d, J=8 Hz, 2H), 0.68 (d, J=5. Hz, 2H), MS (ES) 589 (M+H)⁺ LCMSRT=1.31 min.

Example 1152-(5-(cyclopropylmethyl)-3-(3-(phenylamino)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 485

Using procedures analogous to those described in the preparation of 482,steps 1-3,ethyl-2-[3-(3-bromophenyl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl]-1,3-thiazole-4-carboxylatewas prepared.

Modified Step 4:Ethyl-2-[3-(3-bromophenyl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl]-1,3-thiazole-4-carboxylate(80 mg, 0.139 mmol), powdered K₃PO₄ (56.6 mg, 0.267 mmol), aniline (18μL, 0.199 mmol), and dimethylacetamide (1.3 mL) were combined in a vial.The mixture was then degassed and purged with argon (×3) after whichPd(P(tBu)₃)₂ was added. The vial was then sealed, and the mixture wasstirred at 100° C. for 16 hours. After completion, the reaction mixturewas cooled to room temperature, diluted with EtOAc (40 mL), washed withH₂O (2×10 mL), followed by brine (2×10 mL). The organic layer was thendried over MgSO₄, filtered, and concentrated by rotary evaporator. Thereaction was purified by flash chromatography (Combi-flash Rf,hexane/ethyl acetate, 0-80% gradient) to give the title compound 485 (43mg, 53%). ¹H-NMR (CDCl₃) δ 7.96 (1H, s), 7.72 (2H, d, J=8.3 Hz),7.23-7.18 (6H, m), 7.02-6.99 (4H, m), 6.88 (1H, t, J=7.4 Hz), 4.02 (2H,s), 3.10 (2H, d, J=6.8 Hz), 1.01 (1H, m), 0.33 (2H, dd, J=13.8, 5.8 Hz),0.14 (2H, dd, J=10.2, 5.0 Hz); MS(ES) 585.7 (M+H)+.

Example 1162-(5-cyclopropyl-3-(4-methyl-3-(pyridin-3-yl)phenyl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 499

Using procedures analogous to those described in the preparation of 482,Steps 1-3,2-(3-(3-chloro-4-methylphenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylatewas prepared.

Modified Step 4: A flame dried flask was charged withBis(tri-tert-butylphosphine)palladium (5.1 mg, 10 mol %), cesiumcarbonate (1 mL, 1 M solution), pyridin-3-ylboronic acid (22 mg, 0.2mmol), ethyl2-(3-(3-chloro-4-methylphenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(50 mg, 0.1 mmol), and THF (2 mL). The reaction mixture was microwaveirradiated at 120° C. for 20 min and the solvent was removed by rotaryevaporator. The residue was filtered through a celite pad with MeOH thensolvent was removed by rotary evaporator. The residue was purified byHPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 35% to 85% CH₃CNfor 4 min, 0.1% TFA) to give the title compound 499 (15 mg. 30%). ¹H-NMR(MeOD) δ 8.86 (d, J=5.2 Hz, 1H), 8.83 (s, 1H), 8.45 (d, J=8.4 Hz, 1H),8.27 (s, 1H), 8.13 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64(dd, J=8.0, 1.6 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.29 (s, 2H), 7.27 (s,1H), 4.25 (s, 2H), 2.42-2.34 (m, 1H), 2.33 (s, 3H), 1.10 (dt, J=8.4, 4.6Hz, 2H), 0.69 (dt, J=5.6, 4.6 Hz, 2H); MS (ES) 572.9 (M+H)⁺; LCMSRT=0.87 min.

Example 1172-(3-(3′-amino-6-methyl-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 500

Using procedures analogous to those described in the preparation of 499,the title compound was prepared and purified by HPLC:2-(3-(3′-amino-6-methyl-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 500: ¹H-NMR (MeOD) δ 8.26 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.53 (t,J=8.0 Hz, 1H), 7.49 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H),7.29 (s, 1H), 7.27 (s, 3H), 7.18 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 4.23(s, 2H), 2.41-2.33 (m, 1H), 2.27 (s, 3H), 1.08 (dt, J=8.4, 6.4 Hz, 2H),0.67 (dt, J=5.6, 4.6 Hz, 2H); MS (ES) 586.9 (M+H)⁺; LCMS RT=0.92 min.

Example 1182-(3-(3-(benzyloxy)phenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 501

Using procedures analogous to those described in the preparation of 482,the title compound was prepared and purified by HPLC:2-(3-(3-(benzyloxy)phenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 501: MS (ES) 549.6 (M+H)⁺; LCMS RT=1.16 min.

Example 1192-(5-cyclopropyl-3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 502

Using procedures analogous to those described in the preparation of 482,the title compound was prepared and purified by HPLC:2-(5-cyclopropyl-3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 502: ¹H-NMR (MeOD) δ 8.24 (s, 1H), 7.76 (d, J=8.4 Hz, 2H),7.40-7.31 (m, 4H), 7.19 (d, J=8.4 Hz, 2H), 7.13 (t, J=8.4 Hz, 1H), 7.07(s, 1H), 7.00 (dd, J=8.0, 1.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 4.15 (s,2H), 2.37-2.29 (m, 1H), 1.03 (dt, J=8.4, 6.4 Hz, 2H), 0.62 (dt, J=5.6,4.8 Hz, 2H); MS (ES) 573.6 (M+H)⁺; LCMS RT=0.94 min.

Example 1202-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 467

Route D

Step 1. Synthesis of 1-(3-(cyclopentyloxy)-4-methylphenyl)ethan-1-one

3-Hydroxy-4-methyl acetophenone (1 g, 0.0066 mol) was dissolved inanhydrous DMF and potassium carbonate (7.35 g, 0.053 mol) andcyclopentyl bromide (2.8 mL, 0.026 mol) were added and the reaction wasirradiated at 140° C. for 40 min. The reaction mixture was poured intowater and extracted with ethyl acetate (3×40 mL). The organic layerswere washed with brine (2×50 mL) and dried with anhydrous magnesiumsulfate. The solvents were removed by rotary evaporator and purified byflash chromatography (Combi-flash Rf, hexane/ethyl acetate, 0-50%gradient) to give 1-(3-(cyclopentyloxy)-4-methylphenyl)ethan-1-one (1.20g, 83%).

Step 2. Synthesis of1-(3-(cyclopentyloxy)-4-methylphenyl)-4-cyclopropylbutane-1,3-dione

To a solution of the (1H-benzo[d][1,2,3]triazol-1-yl) derivative (1.20g, 0.0055 mol) in DCM (30 mL) was added magnesium bromidediethyletherate (3.55 g, 0.013 mol) followed by1-(3-(cyclopentyloxy)-4-methylphenyl)ethan-1-one (1.44 g, 0.007 mol) andDIPEA (2.88 mL, 0.016 mol). The reaction mixture was stirred at rt for 2h. The reaction mixture was cooled in an ice bath, quenched with HCl (1M), and extracted with DCM. The DCM layer was washed with HCl (1 M),water, and brine. The crude product was purified by flash chromatography(Combi-flash Rf, hexane/ethyl acetate, 0-20% gradient) to give1-(3-(cyclopentyloxy)-4-methylphenyl)-4-cyclopropylbutane-1,3-dione (0.7g, 42%).

Step 3. Synthesis of4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)-4-cyclopropyl-3-oxobutyl)-benzenesulfonamide

1-(3-(Cyclopentyloxy)-4-methylphenyl)-4-cyclopropylbutane-1,3-dione (0.7g, 0.0023 mol) and cesium carbonate (0.9 g, 0.0028 mol) in DMSO (10 mL)was stirred at rt for 5 minutes then KI (0.42 g, 0.0025 mol) and4-(bromomethyl)benzenesulfonamide (0.63 g, 0.0025 mol) were added. Thereaction mixture was stirred at 50° C. for 5 min After completion of thereaction, the mixture was poured into HCl (1 M) and extracted with ethylacetate. The organic layer was washed with saturated ammonium chlorideand brine. The crude product was purified by flash chromatography(Combi-flash Rf, hexane/ethyl acetate=0-50% gradient) to give4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)-4-cyclopropyl-3-oxobutyl)-benzenesulfonamide(0.82 g, 76%).

Step 4. Ethyl2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

A mixture containing4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)-4-cyclopropyl-3-oxobutyl)benzene-sulfonamide(082 g, 0.0017 mol), p-toluene sulfonic acid (0.16 g, 0.0009 mol),pyrrolidine (71 μL, 0.0009 mol), and ethanol (7 mL) was heated at 90° C.for 1 h. Ethyl 2-hydrazinylthiazole-4-carboxylate (0.41 g, 0.0022 mol)was added and the reaction was heated until completion. The reactionmixture was diluted with ethyl acetate and washed with water and brine.The organic layers were dried with magnesium sulfate and concentrated.The crude product was purified by flash chromatography (Combi-flash Rf,hexane/ethyl acetate, 0-80% gradient) to give ethyl2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylateas a mixture of regioisomers (0.99 g, 93%).

Step 5.2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 467

Ethyl2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(110 mg, 0.18 mmol) was dissolved in THF/MeOH (2 mL: 2 mL) and LiOH (5M, 500 μL) was added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was neutralized by additionof hydrochloric acid (1.2 M), diluted with ethyl acetate (15 mL), washedwith water (10 mL), and dried with anhydrous magnesium sulfate. Theorganic layer was concentrated using a rotary evaporator, dissolved in amixture of DMSO and MeOH, and purified by HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 55% to 90% CH₃CN for 4 min, 0.1% TFA) to givethe title compound 467 (35 mg, 33%). ¹H-NMR (d⁶-DMSO) δ 8.07 (s, 1H),7.53 (d, 2H, J=8 Hz), 7.12-7.07 (m, 5H), 6.95 (d, 1H, J=8 Hz), 6.87 (d,1H, J=8 Hz), 6.63 (s, 1H), 4.16 (m, 1H), 3.90 (s, 2H), 2.93 (m, 2H),1.87 (s, 3H), 1.40-1.29 (m, 8H), 0.91 (m, 1H), 0.11 (m, 2H), 0.014 (m,2H); MS (ES) 593.4 (M+H)⁺ LCMS RT=0.81 min.

Example 1212-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 469

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 469; ¹H-NMR (d⁶-DMSO) δ 8.07 (s, 1H), 7.44 (m, 1H), 7.35 (s, 2H),7.05-6.82 (m, 5H), 3.93 (s, 2H), 3.87-3.43 (m, 6H), 2.93 (m, 2H),1.75-159 (m, 3H), 1.38 (m, 1H), 0.90 (m, 1H), 0.013 (m, 2H) 0.010 (m,2H); MS (ES) 630.9 (M+H)⁺ LCMS RT=1.10 min.

Example 1222-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran-3-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 470

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran-3-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 470 ¹H-NMR (d⁶-DMSO) δ 8.07 (s, 1H), 7.44 (m, 1H), 7.35 (s, 2H),7.04-7.01 (m, 1H), 6.95-6.91 (m, 3H), 6.84-6.82 (m, 1H), 3.92 (s, 2H),3.52-3.50 (m, 4H), 3.40-3.35 (m, 2H), 3.20 (m, 1H), 2.93 (m, 2H), 2.4(m, 1H), 1.77 (m, 1H), 1.39 (m, 1H), 0.91 (m, 1H), 0.013 (m, 2H) 0.010(m, 2H); MS (ES) 552.9 (M+H)⁺ LCMS RT=1.12 min.

Example 1232-(3-(3-cyclopropoxy-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 471

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(3-(3-cyclopropoxy-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 471 ¹H-NMR (d⁶-DMSO) δ 8.07 (s, 1H), 7.46 (m, 1H), 7.37 (s, 2H),7.19 (m, 1H), 7.05-6.85 (m, 5H), 3.92 (s, 2H), 3.50 (m, 1H), 2.93 (m,2H), 0.91 (m, 1H), 0.013 (m, 2H) 0.010 (m, 2H); MS (ES) 586.9 (M+H)⁺LCMS RT=1.12 min.

Example 1242-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 472

Step 1: 1-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)ethan-1-one

In a 20 mL microwave vial, 3-bromo-4-fluro-acetophenone (1 g, 0.0046mol), 4-methylphenyl boronic acid (0.75 g, 0.0055 mol), potassiumcarbonate (1.27 g, 0.009 mol),bis-(di-t-butylphosphinoferrocane)dichloropalladium(II) (150 mg, 5%mol), DMSO (12 mL), and water (4 mL) were added and the vial was purgedwith argon for 5 min. The vial was irradiated at 150° C. for 15 min.After completion of the reaction, the reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith brine and dried with magnesium sulfate. The crude product waspurified by flash chromatography (Combi-flash Rf, hexane/ethyl acetate,0-20% gradient) to give1-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)ethan-1-one (1 g, 90%).

Using procedures analogous to the procedures described to prepare 467,Steps 2-5, the title compound was prepared from1-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)ethan-1-one:2-(5-(cyclopropylmethyl)-3-(6-fluoro-4′-methyl-[1,1′-biphenyl]-3-yl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 472; ¹H-NMR (d⁶-DMSO) δ 8.31 (s, 1H), 7.59-7.35 (m, 11H), 7.17 (m,1H), 4.13 (s, 2H), 3.02 (m, 2H), 2.35 (s, 3H), 1.15 (m, 1H), 0.033 (m,2H) 0.021 (m, 2H); MS (ES) 621.4 (M+H)⁺ LCMS RT=0.79 min.

Example 1252-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((5-(trifluoromethyl)furan-2-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 473

Step 1:1-(4-fluoro-3-((5-(trifluoromethyl)furan-2-yl)methoxy)phenyl)ethan-1-one

A solution of di-t-butyl diazocarboxylate (480 mg, 2 mmol) in THF (11mL) was cooled to 0° C. and triphenyl phosphine (553 mg, 2 mmol) wasadded. (5-(Trifluoromethyl)furan-2-yl)methanol (350 mg, 2 mmol) and3-hydroxy-4-fluoroacetophenone (250 mg, 1.6 mmol) were sequentiallyadded and the cooling was removed. The reaction mixture was stirred for30 min, concentrated by rotary evaporator and purified by flashchromatography (Combi-flash Rf, hexane/ethyl acetate, 0-30% gradient) togive1-(4-fluoro-3-((5-(trifluoromethyl)furan-2-yl)methoxy)phenyl)ethan-1-one(0.66 g, 95%).

Using procedures analogous to the procedures described to prepare 467,Steps 2-5, the title compound 473 was prepared from1-(4-fluoro-3-((5-(trifluoromethyl)furan-2-yl)methoxy)phenyl)ethan-1-one;MS (ES) 694.9 (M+H)⁺ LCMS RT=1.20 min.

Example 1262-(3-(3-(cyclopentyloxy)phenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 477

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(3-(3-(cyclopentyloxy)phenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 477 ¹H-NMR (CDCl₃) δ 8.10 (s, 1H (7.84 (d, J=8.4 Hz, 2H), 7.23-7.31(m, 4H), 7.02-7.07 (m, 2H), 6.88 (dd, J=1.76, 1.8 Hz, 1H) 4.97 (s, 2H),4.11 (s, 2H), 3.15 (d, J=6.64 Hz, 2H), 1.58-1.79 (m, 9H), 1.12-1.16 (m,1H), 0.43 (d, J=8 Hz, 2H), 0.21 (d, J=5.4 Hz, 2H), MS (ES) 579 (M+H)⁺LCMS RT 1.15 min.

Example 1272-(3-(3-(benzyloxy)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 480

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(3-(3-(benzyloxy)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 480 ¹H-NMR (CDCl₃) δ 8.11 (s, 1H), 7.84 (d, J=8 Hz, 2H), 7.24-7.38(m, 8H), 7.15 (d, J=7.4 Hz, 1H) 7.08 (d, J=8 Hz, 2H), 5.01 (s, 2H), 4.95(s, 3H), 4.02 (s, 2H), 3.16 (d, J=6.7 Hz, 2H), 1.11-1.15 (m, 1H), 0.42(d, J=7 Hz, 2H), 0.21 (d, J=5.24 Hz, 2H); MS (ES) 619 (M+H)⁺ LCMSRT=1.28 min.

Example 1282-(5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-3-(3-(4-(trifluoromethyl)phenoxy)-phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 481

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-3-(3-(4-(trifluoromethyl)phenoxy)-phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 481: ¹NMR (CDCl₃) δ 8.11 (s, 1H), 7.8 (d, J=8 Hz, 2H), 7.6 (d, J=8Hz, 2H), 7.21-7.40 (m, 5H), 7.01-7.06 (m, 3H), 5.04 (s, 2H), 4.08 (s,2H), 3.16 (d, J=6 Hz, 2H), 1.09-1.15 (m, 1H) 0.42 (d, J=8. Hz, 2H), 0.21(d, J=5 Hz, 2H), MS (ES) 655 (M+H)⁺ LCMS RT=1.38 min.

Example 1292-(5-(cyclopropylmethyl)-3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 503

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 503; ¹H-NMR (MeOD) δ 8.19 (s, 1H), 7.75 (d, J=8.4 Hz, 2H),7.38-7.31 (m, 4H), 7.20 (d, J=8.4 Hz, 2H), 7.15-7.10 (m, 2H), 7.02-6.97(m, 1H), 7.00 (dd, J=8.0, 1.2 Hz, 2H), 4.10 (s, 2H), 3.22 (d, J=6.8 Hz,2H), 1.12-1.06 (m, 1H), 0.39-0.33 (m, 2H), 0.21 (dt, J=6.0, 5.2 Hz, 2H);MS (ES) 587.7 (M+H)⁺; LCMS RT=1.00 min.

Example 1302-(5-(cyclopropylmethyl)-3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 504

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 504; MS (ES) 552.6 (M+H)⁺; LCMS RT=0.98 min.

Example 1312-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((4-fluorobenzyl)oxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 527

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((4-fluorobenzyl)oxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 527; ¹H-NMR (MeOD) δ 8.21 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.40 (m,2H), 7.31 (d, J=8.3 Hz, 2H), 7.23 (m, 1H), 7.17 (m, 1H), 7.107 (m, 3H),4.96 (s, 2H), 4.13 (s, 2H), 3.25 (d, J=6.83 Hz, 2H), 1.12 (m, 1H), 0.38(d, J=8.1 Hz, 2H), 0.23 (d, J=5.1 Hz, 2H); MS (ES) 636.9 (M+H)⁺; LCMSRT=1.12 min.

Example 1322-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((3-fluorobenzyl)oxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 528

Using procedures analogous to those described in the preparation of 467,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((3-fluorobenzyl)oxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 528; ¹H-NMR (MeOD) δ 8.19 (s. 1H), 7.77 (t, J=7.7 Hz, 1H). 7.40 (m,1H), 7.23 (m, 3H), 7.16 (m, 2H), 7.04 (m, 3H), 5.08 (s, 2H), 4.11 (s,2H), 3.25 (d, J=6.5 Hz), 1.11 (m, 1H), 0.39 (d, J=7.8 Hz), 0.23 (d,J=4.6 Hz); MS (ES) 655.0 (M+H)⁺; LCMS RT=1.19 min.

Example 1334-((3-(cyclopropylmethyl)-5-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)-1-(4-((oxo-13-methyl)-13-oxidanyl)thiazol-2-yl)-1H-pyrazol-4-yl)methyl)benzenesulfonamide525

Using procedures analogous to those described in the preparation of 482,the title compound was prepared and purified by HPLC:4-((3-(cyclopropylmethyl)-5-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)-1-(4-((oxo-13-methyl)-13-oxidanyl)thiazol-2-yl)-1H-pyrazol-4-yl)methyl)benzenesulfonamide525: ¹H-NMR (CDCl3) δ 7.96 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.39 (m,2H), 7.24 (m, 4H) 7.06 (m, 4H), 3.93 (s, 2H) 2.53 (d, J=6.8 Hz, 2H),1.05 (m, 1H), 0.55 (m, 2H), 0.22 (d, J=5.8 Hz, 2H); MS (ES) 607.0(M+H)⁺; LCMS RT=0.95 min.

Example 1342-(5-(cyclopropylmethyl)-3-(3-(4-fluorophenoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 507

Step 1: 1-(3-(4-fluorophenoxy)phenyl)ethan-1-one

A mixture of 1-(3-hydroxyphenyl) ethan-1-one (1.0 g, 7.34 mmol),(4-fluorophenyl)boronic acid (2.06 g, 14.7 mmol), Cu(OAc)₂ (2.67 g, 14.7mmol), and pyridine (1.18 mL, 14.7 mmol) in dichloromethane (20 mL) wasstirred at room temperature for 48 h then quenched with water (25 mL),extracted with dichloromethane, and dried over MgSO₄. The residue waspurified by flash chromatography (Combi-flash Rf, hexane/ethyl acetate,0-40% gradient) to give the title compound (0.56 g, 30%). ¹H-NMR (CDCl3)δ (ppm) 7.67 (dt, J=7.6, 1.2 Hz, 1H), 7.53 (t, J=2.0 Hz, 1H), 7.42 (t,J=8.0 Hz, 1H), 7.67 (dq, J=8.0, 0.8 Hz, 1H), 7.08-6.97 (m, 4H), 2.58 (s,3H).

Step 2:

Using procedures analogous to those described in the preparation of 467,Steps 2-5, the title compound was prepared from1-(3-(4-fluorophenoxy)phenyl)ethan-1-one and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(3-(4-fluorophenoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 507 ¹H-NMR (MeOD) δ (ppm) 8.14 (s, 1H), 7.78 (d, J=8.4 Hz, 2H),7.40 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.10-7.04 (m, 2H),7.01-6.96 (m, 4H), 6.84 (t, J=2.0 Hz, 1H), 3.92 (s, 2H), 2.46 (d, J=7.2Hz, 2H), 1.00-0.90 (m, 1H), 0.44 (ddd, J=8.4, 6.0, 4.4 Hz, 2H), 0.13(dd, J=10.0, 4.4 Hz, 2H); MS (ES) 605.2 (M+H)⁺; LCMS RT=1.20 min.

Example 1352-(5-(cyclopropylmethyl)-3-(4-fluoro-3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 508

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 508; ¹H-NMR (d⁶-DMSO) δ 7.63 (d, J=8.4 Hz, 2H), 7.42-7.33 (m, 4H),7.23 (s, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.90 (d,J=7.6 Hz, 2H), 4.06 (s, 2H), 3.12 (d, J=6.8 Hz, 2H), 0.87-0.80 (m, 1H),0.30 (ddd, J=10.0, 6.0, 4.4 Hz, 2H), 0.13 (dd, J=10.0, 5.2 Hz, 2H); MS(ES) 605.2 (M+H)⁺; LCMS RT=1.18 min.

Example 1362-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(3-fluorophenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 509

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(3-fluorophenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 509; ¹H-NMR (MeOD) δ 8.20 (s, 1H), 7.72 (t, J=8.0 Hz, 1H),7.50-7.46 (m, 1H), 7.37-7.25 (m, 3H), 6.99 (s, 1H), 6.98 (d, J=16.8 Hz,1H), 6.88 (dt, J=8.4, 2.0 Hz, 1H), 6.73 (dt, J=10.0, 2.0 Hz, 1H), 6.66(dd, J=8.4, 2.4 Hz, 1H), 4.13 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.13-1.05(m, 1H), 0.44 (ddd, J=8.0, 5.6, 4.0 Hz, 2H), 0.22 (dd, J=10.4, 5.2 Hz,2H); MS (ES) 640.9 (M+H)⁺; LCMS RT=1.19 min.

Example 1372-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(p-tolyloxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 510

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(p-tolyloxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 510; ¹H-NMR (MeOD) δ 8.19 (s, 1H), 7.70 (t, J=8.4 Hz, 1H),7.44-7.40 (m, 1H), 7.25 (dd, J=10.8, 8.8 Hz, 1H), 7.17-7.12 (m, 3H),6.93 (s, 1H), 6.92 (d, J=17.6 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 4.07 (s,2H), 3.22 (d, J=6.8 Hz, 2H), 1.11-1.04 (m, 1H), 0.37 (ddd, J=8.0, 6.0,4.8 Hz, 2H), 0.21 (dd, J=10.4, 5.2 Hz, 2H); MS (ES) 636.9 (M+H)⁺; LCMSRT=1.12 min.

Example 1382-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-fluorophenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 511

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-fluorophenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 511; ¹H-NMR (MeOD): δ 8.19 (s, 1H), 7.71 (t, J=8.8 Hz, 1H),7.45-7.41 (m, 1H), 7.26 (dd, J=8.8, 11.0 Hz, 1H), 7.15 (dd, J=2.2, 7.9Hz, 1H), 7.09 (dd, J=8.5, 9.0 Hz, 2H), 6.98-6.89 (m, 4H), 4.09 (s, 2H),3.23 (d, J=7.05 Hz, 2H), 1.13-1.04 (m, 1H), 0.40-0.35 (m, 2H), 0.23-0.19(m, 2H); MS (ES) 641.0 (M+H)⁺; LCMS RT=1.18 min.

Example 1392-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 512

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 512; ¹H-NMR (MeOD) δ 8.28 (s, 1H), 7.73-7.67 (m. 3H), 7.52-7.48 (m,1H), 7.38 (dd, J=2.1, 7.6 Hz, 1H), 7.30 (dd, J=8.5, 10.5 Hz, 1H),7.03-6.96 (m, 4H), 4.16 (s, 2H), 3.27 (d, J=6.8 Hz, 2H), 1.18-1.08 (m,1H), 0.42-0.38 (m, 2H), 0.26-0.23 (m, 2H); MS (ES) 691.0 (M+H)⁺; LCMSRT=1.24 min.

Example 1402-(5-(cyclopropylmethyl)-3-(3-(3-fluorophenoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 526

Using procedures analogous to those described in the preparation of 507,the title compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(3-(3-fluorophenoxy)phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 526; ¹H-NMR (MeOD) δ 7.89 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.42 (m,2H), 7.34 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.12 (m, 1H) 8.87 (m, 2H),6.70 (m, 2H), 4.13 (s, 2H), 3.25 (d, J=6.7 Hz, 2H), 0.32 (d, J=8.2 Hz,2H), 0.12 (d, J=4.39 Hz, 2H); MS (ES) 605.2 (M+H)⁺; LCMS RT=1.21 min.

Example 1412-(5-(cyclopropylmethyl)-3-(3′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 505

Route E

Using procedures similar to the procedures described to prepare 467,Steps 1-3, ethyl2-(3-(3-bromo-5-methylphenyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylatewas prepared.

Step 4.2-(5-(cyclopropylmethyl)-3-(3′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

A flame dried flask was charged withbis(tri-tert-butylphosphine)palladium (4.0 mg, 10 mol %), cesiumcarbonate (0.5 mL, 1 M solution), (3-fluorophenyl)boronic acid (23 mg,0.162 mmol), pyrazole regioisomer (50 mg, 0.081 mmol), and THF (2 mL).The reaction mixture was microwave irradiated at 120° C. for 20 min andthe solvent was removed by rotary evaporator. After saponification andneutralization, the residue was purified by HPLC (Phenomenex Gemini C18,H₂O/CH₃CN gradient from 40% to 90% CH₃CN for 4 min, 0.1% TFA) to givethe title compound 505 (10 mg, 21%). MS (ES) 603.7 (M+H)⁺; LCMS RT=1.26min.

Example 1422-(5-(cyclopropylmethyl)-3-(4′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 506

Using procedures similar to the procedures described to prepare 505, thetitle compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(4′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 506; MS (ES) 603.4 (M+H)⁺; LCMS RT=1.26 min.

Example 1432-(5-(cyclopropylmethyl)-3-(5-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 478

Using procedures similar to the procedures described to prepare 505, thetitle compound 478 was prepared and purified by HPLC; ¹NMR (CDCl₃) δ8.10 (s, 1H) 7.86 (d, J=8.32 Hz, 2H) 7.23-7.29 (m, 7H), 7.00 (d, J=7.12Hz, 1H), 6.91 (dd, J=1.88 1.88 Hz, 1H), 6.60 (t, J=3.92 Hz, 1H), 4.96(s, 2H), 4.11 (s, 2H)), 3.87 (s, 3H), 3.21 (d, J=6.64 Hz, 2H) 1.17-1.25(m, 1H) 0.47 (d, J=7.28 Hz, 2H), 0.24 (d, J=5.2 Hz, 2H), MS: (ES) 619(M+H)⁺ LCMS RT 1.32 min.

Example 1442-(5-(cyclopropylmethyl)-3-(4′,5-difluoro-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 479

Using procedures similar to the procedures described to prepare 505, thetitle compound was prepared and purified by HPLC:2-(5-(cyclopropylmethyl)-3-(5-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 479; MS (ES) 607 (M+H)⁺ LCMS RT 1.35 min.

Example 145

Step 1: General Synthesis of ethyl2-(3-(3-substituted-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

Method A—

Dioxane (2 mL) and water (0.5 mL) were added to a mixture of ethyl2-(3-(3-bromo-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbox-ylate(0.2 mmol. 1 eq), potassium phosphate (0.4 mmol, 2 eq), S-PHOS (5 mol%), SPhos Palladacycle G3 (2.5 mol %) and appropriate boronic acid/esteror potassium trifluoroborate in a sealed microwave vial. The reactionmixture was bubbled with argon for few minutes then stirred at 100° C.in a preheated heating block for 1-6 h. Upon completion of the reactionas detected by LCMS, the reaction mixture was cooled and stirred with ametal scavenger for 1 h. The reaction mixture was then diluted withethyl acetate and filtered through a pad of celite. The filtrate wasconcetrated and purified directly on silica using gradient elution(20-40% ethyl acetate in hexanes).

Method B—

A mixture of ethyl 2-(3-(3-bromo-4-substitutedphenyl)-5-(substituted)-4-(3/4-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(1 mmol), tri(tert-butylphosphonium)tetrafluoroborate (10 mol %),allylpalladium chloride dimer (5 mol %) and DABCO (2 mmol, 2 eq) indioxane (0.5 molar concentration) was bubbled with argon for 5 minutes.The appropriate alkyne (1.5 mmol, 1.5 eq) was added and the reactionmixture was stirred at room temperature overnight. After completion ofthe reaction, silica bound palladium scavenger was added and the slurrywas stirred at room temperature for 1 hr, subsequently diluted withethyl acetate and filtered through a pad of celite. The filtrate wasconcentrated and the residue was purified directly on silica usinggradient elution (20-40% ethyl acetate in hexanes) yielding the desiredcompound which was taken to the next step.

Step 2:2-(3-(3-substituted-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

The titled compound was synthesized and purified in a similar manner asdescribed in Example 18.

Example 146

Step 1: General Synthesis of ethyl2-(3-(3-substituted-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxy-lateUsing NEGISHI Coupling

A mixture of ethyl2-(3-(3-bromo-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbox-ylate(1 eq) (0.1 g, 0.157 mmol), CPhos (5 mol %), CPhos Pdcycle G3 (Sigma cat#763004, 2.5 mol %) in a Biotage microwave vial was backfilled withargon then added a THF solution of appropriate alkyl/cycloalkyl zinchalide (3-5 eq) under argon. The reaction mixture was stirred at roomtemperature or at 60° C. for 0.5-3 h. After completion, the reactionmixture was quenched with 1 molar HCl and extracted with ethyl acetate.The organic layer was washed with bicarbonate and brine subsequentlydried under magnesium sulfate. The crude material was purified directlyon silica using gradient elution (10-40% EA in hexanes over 20 columnvolumes).

Step 2: General Synthesis of ethyl2-(3-(3-substituted-4-substitutedphenyl)-5-(cyclopropylmethyl)-4-(3-substituted-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcids

The titled compound was synthesized and purified in a similar manner asdescribed in Example 18.

Example 147

This example describes the synthesis of2-(5-(hydroxy)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids in an embodiment of the invention.

Step 1: Synthesis of Ethyl 3-oxo-3-phenylpropanoates

Ethyl acetate (102 mmol) was added dropwise to a cooled solution oflithium stirred for 30 minutes at which time the appropriate benzoylchloride (56.6 mmol) was added after which the reaction was allowed toattain rt. Upon completion as detected by LCMS, the reaction wasquenched with sat. aq. NH₄Cl. The product was extracted with ethylacetate and the organic layer washed with water and brine, dried overNa₂SO₄, filtered, and concetrated under reduced pressure. The residuewas purified directly on silica using gradient elution (5-50% ethylacetate in hexanes over 12 CV). The resulting yellow oils were used inthe next step without further purification or characterization.

Step 2: Synthesis of Ethyl3-oxo-3-phenyl-2-(4-sulfamoylbenzyl)propanoates

Ethyl 3-oxo-3-phenylpropanoate (150 mmol) and cesium carbonate (Cs₂CO₃,226 mmol) were dissolved in DMSO (50 ml). The reaction mixture wasstirred at rt for 10 minutes at which time potassium iodide were added(KI, 150 mmol) and 4-(bromomethyl)-benzenesulfonamides (165 mmol). Theresulting mixture was stirred at rt for 1 h. Upon completion as detectedby LCMS, the reaction mixture was diluted with a large excess of ethylacetate and filtered through celite. The filtrate was washed with 1 MHCl, sat aq NH₄Cl and brine, dried over Na₂SO₄, filtered, andconcetrated under reduced pressure. The residue was purified directly onsilica using gradient elution (20-40% ethyl acetate in hexanes over 16CV).

Step 3: ethyl2-(5-hydroxy-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylates

A solution of ethyl 3-oxo-3-phenyl-2-(4-sulfamoylbenzyl)propanoate (6.7mmol), ethyl 2-hydrazinylthiazole-4-carboxylate, 2 HBr (7.3 mmol) andp-toluene sulfonic acid (pTsOH, 20 mmol) in dioxane was heated in asealed vessel in the microwave for 15 min at 160° C. Upon completion asdetected by LCMS, the reaction mixture was diluted with ethyl acetateand filtered through celite. The solvent was removed under reducedpressure and the crude product was purified directly on silica usinggradient elution (0-100% ethyl acetate in hexanes over 15 CV).

Step 4: Synthesis of2-(5-hydroxy-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids

To a solution of ethyl2-(5-hydroxy-3-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.07 mmol) in THF/MeOH was added 1.5 M LiOH (0.27 mmol). The reactionmixture was stirred at rt for 1 h. Upon completion as detected by LCMS,the solvent was removed by forced air. The residue was taken into DMSOand purified directly via preparative reverse phase using gradientelution (4-100% acetonitrile modified with 0.1% TFA in water modifiedwith 0.1% TFA). The product fractions were directly frozen andlyophilized overnight, yielding an off-white powder.

Example 148

This example describes the synthesis of2-(5-(hydroxy)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacids in an embodiment of the invention.

Step 1: Synthesis of4-((5-amino-1-substituted-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide

A solution of ethyl 2-hydrazinyl-5-methylthiazole-4-carboxylate (0.267mmol), 4-(2-cyano-3-oxo-3-phenylpropyl)benzenesulfonamide (0.267 mmol)and tosic acid (0.534 mmol) in MeOH was heated in the microwave for 15min. The crystals upon cooling was collected by filtration and washedwith ethanol and dried used as such in the next step.

Step 2:2-(5-amino-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)-5-methylthiazole-4-carboxylicacid

The titled compound was synthesized and purified in a similar manner asdescribed in Example 18

Example 149

This example describes the synthesis of4-(((5-hydroxy-3-phenyl-1H-pyrazol-4-yl)methyl)amino)benzenesulfonamidein an embodiment of the invention.

Step 1: Synthesis of 3-phenyl-1H-pyrazol-5-ol

To a solution of ethyl 3-oxo-3-phenylpropanoate (24.7 mmol) in ethanol(15 ml) was added hydrazine hydrate (49 mmol) at 0° C., then stirred atrt for 1 h. Upon completion, the product was extracted with ethylacetate, washed with water, bicarbonate and brine, dried over Na₂SO₄,filtered, and concetrated under reduced pressure. The crude productobtained after evoporating the solvent was used as such in the nextstep.

Step 2:4-(((5-hydroxy-3-phenyl-1H-pyrazol-4-yl)methyl)amino)-benzenesulfonamide

3-phenyl-1H-pyrazol-5-ol (0.5 g, 3.12 mmol and 4-aminobenzenesulfonamide(0.538 g, 3.12 mmol) in EtOH (Volume: 6.24 ml) was stirred in a sealedtube at 100° C. for 1 h. The product precipitated upon cooling, and theslurry was sonicated for 5 minutes and filtered. The precipitate waswashed with ethanol, re-suspended in DMSO and purified directly onreverse phase using gradient elution (4-100% acetonitrile modified with0.1% TFA in water modified with 0.1% TFA).

Example 150

This example describes the synthesis of2-(3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid in an embodiment of the invention.

Step 1: Synthesis of1-(3,4-difluorophenyl)-4,4,4-trifluorobutane-1,3-dione

A stirring solution of 1-(3,4-difluorophenyl)ethanone (3.20 mmol) in DMF(6 ml) was chilled to 0° C. before NaH (3.8 mmol) was added portionwise.The reaction mixture was stirred for 30 minutes at which time ethyl2,2,2-trifluoroacetate (3.84 mmol) was added and the reaction mixturewas allowed to attain rt. Upon completion the reaction was quenched withwater the pH was adjusted with 1 N HCl and the product was extractedwith ethyl acetate. The organic layer was washed with water and brine,dried over Na₂SO₄, filtered, and concetrated under reduced pressure. Theresidue was purified directly on silica using gradient elution (5-50%ethyl acetate in hexanes over 12 CV) to provide a yellow oil.

Step 2: Synthesis of2-(3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

A solution of 1-(4-chlorophenyl)-4,4,4-trifluorobutane-1,3-dione (3.99mmol) and hydrazinecarbothioamide (3.99 mmol) in EtOH was refluxed for12 h. The solvent was removed under reduced pressure and the residue wasboiled in chloroform and filtered. The filtrate was concentrated andtaken up EtOH then added ethyl 3-bromo-2-oxopropanoate (3.99 mmol) andrefluxed for 1 h. Added concentrated sulfuric acid and refluxedovernight. The solvent was concentrated and the product extracted withethyl acetate. The organic layer was washed with bicarbonate and brine,dried over Na₂SO₄, filtered, and concetrated under reduced pressure. Thecrude product containing the mixture of products was purified on reversephase preparative column. The second peak was collected and hydrolyzedwith HCl/AcOH at 120° C. in a sealed tube for 1 h. After removing thesolvent with forced air the crude product were purified directly onreverse phase preparative column (4-100% acetonitrile modified with 0.1%TFA in water modified with 0.1% TFA).

Example 151

This example describes the synthesis of2-(3-(3,4-difluorophenyl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid and3-(3,4-difluorophenyl)-1-(4-(methoxycarbonyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid in an embodiment of the invention

Step 1: Synthesis of Ethyl 4-(3,4-difluorophenyl)-2,4-dioxobutanoate

A solution of NaOEt (144 mmol) in ethanol was added1-(3,4-difluorophenyl)ethanone (96 mmol) was stirred for 5 minutes atwhich time diethyl oxalate (106 mmol) was added. The reaction mixturewas stirred for 10 minutes and a thick ppt was formed. The reactionmixture was poured into ice water containing 7 mL of conc HCl. Aprecipitate formed and was collected by filtration and washed with waterand dried under air. The crude product was used as such in the nextstep.

Step 2: Synthesis of Ethyl3-(3,4-difluorophenyl)-1H-pyrazole-5-carboxylate

To a solution of ethyl 4-(3,4-difluorophenyl)-2,4-dioxobutanoate (90mmol) in ethanol was added hydrazine monohydrate (99 mmol) and thereaction mixture was stirred at rt for 12 h. The reaction becomes clearsolution and eventually the product precipitates. The solvent wasremoved and the desired compound was purified by recrystalization inethanol.

Step 3: Synthesis of (3-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methanol

To a solution of ethyl 3-(3,4-difluorophenyl)-1H-pyrazole-5-carboxylate(5.67 mmol) in THF (20 ml) was added lithium aluminum hydride (11.34mmol, 1.0 M in THF) slowly dropwise at 0° C. The reaction mixture wasstirred for 1 h then quenched with sat. aq. NH₄Cl. The product wasextracted with ethyl acetate and the organic layer washed with water andbrine, dried over Na₂SO₄, filtered, and concetrated under reducedpressure. The residue was purified directly on silica using gradientelution (50-100% EA in hexanes).

Step 4: Synthesis of tert-butyl2-(3-(3,4-difluorophenyl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

A solution of (3-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methanol (0.952mmol), tert-butyl 2-bromothiazole-4-carboxylate (1.047 mmol),(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.190 mmol), Cut (0.095mmol) and K₃PO₄ (2.093 mmol) in dioxane was stirred at 110° C. in asealed tube for 12 h. Upon completion the reaction mixture was stirredwith thiol resin and filtered through celite and the celite pad waswashed with ethyl acetate. After concentration the crude product waspurified directly on silica using gradient elution (10-50% ethyl acetatein hexanes) providing a white solid.

Step 5: Synthesis of2-(3-(3,4-difluorophenyl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

Tert-butyl2-(3-(3,4-difluorophenyl)-5-(hydroxymethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylatewas deprotected with TFA/DCM. The product was purified directly onreverse phase preparative column (4-100% acetonitrile modified with 0.1%TFA in water modified with 0.1% TFA).

Step 6: Synthesis of3-(3,4-difluorophenyl)-1-(4-(methoxycarbonyl)thiazol-2-yl)-1H-pyrazole-5-carboxylicacid

To a 5 dram vial were added methyl2-(3-(3,4-difluorophenyl)-5-formyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.014 g, 0.04 mmol) and Oxone (0.025 g, 0.04 mmol). The reactionmixture was stirred at rt for 16 hr. The reaction was complete by LCMS.The reaction mixture was diluted with water and the product wasextracted with EtOAc. The org layer was dried with brine and Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified directly on reverse phase preparative column (4-100%acetonitrile modified with 0.1% TFA in water modified with 0.1% TFA).

Example 152

This example describes the synthesis of2-(3-([1,1′-biphenyl]-3-yl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxamide70 in an embodiment of the invention.

A stirring solution of ethyl2-(3-([1,1′-biphenyl]-3-yl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.019 mmol) and MeOH (0.5 ml) at 0° C. was bubbled with ammonia gas for1 min. The reaction mixture was heated to 60° C. for 30 min. Uponcompletion, the reaction mixture was purified directly on reverse phasepreparative column (4-100% acetonitrile modified with 0.1% TFA in watermodified with 0.1% TFA).

Example 153

This example describes the synthesis of4-((1-(4-(1H-tetrazol-5-yl)thiazol-2-yl)-3-([1,1′-biphenyl]-3-yl)-5-hydroxy-1H-pyrazol-4-yl)methyl)benzenesulfonamide72 in an embodiment of the invention.

Step 1: Synthesis of4-((3-([1,1′-biphenyl]-3-yl)-1-(4-cyanothiazol-2-yl)-5-hydroxy-1H-pyrazol-4-yl)methyl)benzenesulfonamide

To a stirring solution of2-(3-([1,1′-biphenyl]-3-yl)-5-hydroxy-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxamide(0.344 mmol) and diisopropylethylamine (1.030 mmol) in CH₂Cl₂ (3.4 mL)was added TFAA (0.687 mmol) dropwise at 0° C. The reaction mixture wasstirred at rt for 5 hr. An additional 2 eq. of TFAA (0.687 mmol) and 3eq of diisopropylethylamine (1.030 mmol) were added and the reactionmixture was stirred overnight. Upon completion, the reaction was dilutedwith CH₂Cl₂, washed with water, NaHCO₃, and brine. The organic layer wasdried over MgSO₄ and concentrated under reduced pressure and the residuewas purified directly on reverse phase preparative column (4-100%acetonitrile modified with 0.1% TFA in water modified with 0.1% TFA).

Step 2: Synthesis of4-((1-(4-(1H-tetrazol-5-yl)thiazol-2-yl)-3-([1,1′-biphenyl]-3-yl)-5-hydroxy-1H-pyrazol-4-yl)methyl)benzenesulfonamide

A solution of N-((4(3-([1,1′-biphenyl]-3-yl)-1-(4-cyanothiazol-2-yl)-5-hydroxy-1H-pyrazol-4-yl)methyl)phenyl)sulfonyl)-2,2,2-trifluoroacetamide(0.036 mmol), sodium azide (0.108 mmol) and NH₄Cl (0.072 mmol) heated to125° C. in DMF (0.4 ml) for 2 h. Upon completion, the reaction mixturewas purified directly on reverse phase preparative column (4-100%acetonitrile modified with 0.1% TFA in water modified with 0.1% TFA).

Example 154

This example describes the synthesis of2-(3-phenyl-5-(pyridin-3-ylamino)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 80 in an embodiment of the invention.

A mixture of ethyl2-(5-iodo-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.168 mmol), pyridin-3-amine (0.252 mmol), XantPhos (0.168 mmol),Pd₂(dba)₃ (0.168 mmol) and sodium tert-butoxide (0.370 mmol) in amicrowave vial was degassed with argon. 2 mL of dioxane was added andstirred at 100° C. overnight. The solvent was removed by forced air. Thecontents were suspended in DMSO and stirred with silica palladiumscavenger at 70° C. for 1 h then filtered through a syringe filter. Thecrude product was hydrolyzed according to Example 18 and was purifieddirectly on reverse phase preparative column (4-100% acetonitrilemodified with 0.1% TFA in water modified with 0.1% TFA).

Example 155

This example describes the synthesis of2-(3-phenyl-4-((4-sulfamoylpiperazin-1-yl)methyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 90 and2-(3-phenyl-4-((piperazine-1-sulfonamido)methyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid 138 in an embodiment of the invention.

Step 1: Synthesis of Tert-Butyl2-(4-formyl-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

A solution of 3-phenyl-1H-pyrazole-4-carbaldehyde (2.323 mmol), K₂CO₃(3.48 mmol), and tert-butyl 2-bromothiazole-4-carboxylate (2.439 mmol)in DMSO was stirred for 3 h. Upon completion the product was extractedwith ethyl acetate, washed with sat. aq. NH₄Cl, water and brine, driedover Na₂SO₄, filtered, and concetrated under reduced pressure. Theresidue was purified directly on silica using gradient elution (50-100%EA in hexanes) providing a yellow solid.

Step 2: Synthesis of2-(3-phenyl-4-((4-sulfamoylpiperazin-1-yl)methyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 90 and2-(3-phenyl-4-((piperazine-1-sulfonamido)methyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid 138

A mixture of tert-butyl2-(4-formyl-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (0.422 mmol)and piperazine-1-sulfonamide (0.633 mmol) in methanol (2 mL) was stirredat 90° C. for 15 minutes in a sealed tube. The reaction mixture wascooled to room temperature then treated with sodium cyanoborohydride(0.844 mmol) and stirred at rt for another 1 h. The mixture of productswas extracted with ethyl acetate. The organic layer was subsequentlywashed with water and brine. Upon removal of the solvent, the productwas taken in dichloromethane (1 mL) and treated with TFA (0.5 mL) thenstirred at rt for 1 h. The solvent was removed by forced air and thecrude product was subsequently purified on a preparative HPLC.

Example 156

This example describes the synthesis of alkyl2-(3-(3,4-difluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)thiazole-4-carboxylateand alkyl2-(3-(3,4-difluorophenyl)-5-alkyloxy-1H-pyrazol-1-yl)thiazole-4-carboxylatein an embodiment of the invention.

To a stirring solution of2-(3-(3,4-difluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (0.155 mmol) in DMA (0.8 mL) were added 1-chloroethyl ethylcarbonate (0.155 mmol) and K₂CO₃ (0.309 mmol). The reaction mixture wasstirred at rt for 2 h. Upon completion the reaction mixture was filteredand the filtrate was subsequently purified on a preparative HPLC.

Example 157

This example describes the synthesis of2-(3,4-difluorophenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]thieno[3,2-e]pyrimidine-6-carboxylicacid 116 in an embodiment of the invention

Step 1: Synthesis of 3-ethyl 4-methyl2-hydrazinylthiophene-3,4-dicarboxylate

A solution of 3-ethyl 4-methyl 2-aminothiophene-3,4-dicarboxylate (4.86g, 21.20 mmol, 1 eq) in conc. HCl (30 ml) was added sodium nitrite(1.609 g, 23.32 mmol, 1.1 eq) in 15 mL of water drop wise at 0° C. Thereaction mixture was stirred for 30 min then added a solution of tin(II)chloride (16.08 g, 85 mmol, 4 eq) in 15 mL of conc. HCl and stirred for15 minutes. The reaction mixture was carefully neutralized with 40% NaOHsolution upon cooling in an ice bath. The solid tin salt was removed byfiltration and the filtrate was extracted with ethyl acetate. Theorganic layer was washed with brine and dried over sodium sulfate. Thecrude product was purified on a flash system using a 220 G gold silicacolumn eluting with 20-100% ethyl acetate in hexanes. The first peakwith mass M+H=245 was pooled and concentrated to get a light yellowsolid (1.36 g in 26% yield).

Step 2: Synthesis of methyl2-(3,4-difluorophenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]thieno[3,2-e]pyrimidine-6-carboxylate115

A thoroughly mixed mixture of 3-ethyl 4-methyl2-hydrazinylthiophene-3,4-dicarboxylate (0.3 g, 1.228 mmol, 1 eq) and3-(3,4-difluorophenyl)-3-oxopropanenitrile (0.222 g, 1.228 mmol, 1 eq)in an open vial was stirred neat at 130° C. for 1.5 h. The melted liquidbecomes thick solid which is triturated in DCM/MeOH. The crude productwas purified on flash system using a 24 g silica column eluting with1-10% methanol in DCM over 12 column volumes. The pure fraction waspooled and concentrated to get 0.49 g (Yield=84%) of white solid.

Step 3: Synthesis of2-(3,4-difluorophenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]thieno[3,2-e]pyrimidine-6-carboxylicacid 116

A solution methyl2-(3,4-difluorophenyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]thieno[3,2-e]pyrimidine-6-carboxylate(0.1 g, 0.277 mmol, 1 eq) in a mixture of THF/MeOH (3/1) was treatedwith 1.5 molar solution of LiOH in water (4-5 eq) then stirred at roomtemperature for 1 h. The excess solvent was removed by forced air thenthe residue was acidified with 1 molar HCl. The crude product was takenin DMSO and purified on a preparative HPLC.

Example 158

This example describes the synthesis of2-(3-phenyl-4-((4-sulfamoylbenzyl)amino)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid and2-(3-phenyl-4-(4-sulfamoylbenzamido)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid in an embodiment of the invention

Step 1: Synthesis of Tert-Butyl2-(4-amino-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

A solution of 3-phenyl-1H-pyrazol-4-amine (0.25 g, 1.57 mmol), K₂CO₃(0.33 g, 2.36 mmol), and tert-butyl 2-bromothiazole-4-carboxylate (0.47g, 1.73 mmol) in DMSO was stirred for 24 h at 120° C. Upon completionthe reaction mixture was cooled, diluted with ethyl acetate and filteredthrough celite. The organic layer was washed with ammonium chloride andbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified directly on silica gel using gradientelution (5-80% ethyl acetate containing 1% TEA in hexanes over 15 CV) toafford the desired compound as a yellow solid.

Step 2—Method A—Synthesis of2-(3-phenyl-4-((4-sulfamoylbenzyl)amino)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

To a stirring solution of tert-butyl2-(4-amino-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (0.13 g, 0.38mmol) and 4-formylbenzenesulfonamide (0.09 g, 0.49 mmol) in MeOH (3 ml)was added few drops of acetic acid. The reaction mixture was stirred at80° C. for 30 minutes in a sealed tube. The reaction mixture was cooledto rt then added sodium cyanoborohydride (0.048 g, 0.759 mmol) andstirred at rt for another 15 minutes. The crude reaction mixture waspurified directly on reverse phase preparative chromatography withoutworkup using gradient elution (4-100% acetonitrile modified with 0.1%TFA in water modified with 0.1% TFA). The pure product was deprotectedwith TFA/DCM finally purified on HPLC.

Step 2—Method B—Synthesis of2-(3-phenyl-4-(4-sulfamoylbenzamido)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid

A solution of 4-sulfamoylbenzoic acid (0.09 g, 0.44 mmol) and HATU (0.22g, 0.58 mmol) in DMF was stirred at rt for 15 minutes at which timetert-butyl 2-(4-amino-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.1 g, 0.29 mmol) and Hunig'sBase (0.10 ml, 0.58 mmol) were added. Thereaction mixture was stirred at 60° C. for 4 h. Upon completion thereaction mixture was cooled and extracted with ethyl acetate. Theorganic layer was washed with water, bicarbonate and brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified directly on silica gel using gradient elution (20-100%ethyl acetate in hexanes over 15 CV). The first fraction was collectedand dried. The pure product was deprotected with TFA/DCM, dried usingforced air then taken up in DMSO and finally purified on HPLC.

Example 159

This example describes the synthesis of4-((3-phenyl-1-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazol-2-yl)-1H-pyrazol-4-yl)methyl)benzenesulfonamidein an embodiment of the invention

Step 1: Synthesis of4-((1-(4-formylthiazol-2-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide

To a stirring solution of4-((1-(4-(hydroxymethyl)thiazol-2-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(0.36 g, 0.84 mmol) in CHCl₃ (10 mL) was added manganese dioxide (0.37g, 4.2 mmol). The reaction mixture was stirred at rt for 12 h. Uponcompletion the solution was filtered through celite and concentratedunder reduced pressure to afford the title compound. The crude productwas taken to the next step without purification.

Step 2: Synthesis of4-((3-phenyl-1-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazol-2-yl)-1H-pyrazol-4-yl)methyl)benzenesulfonamide

To a stirring solution of4-((1-(4-formylthiazol-2-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide(0.15 g, 0.35 mmol) in THF (2 ml) was added(trifluoromethyl)trimethylsilane (0.16 ml, 1.060 mmol) followed by TBAF(0.18 ml, 0.18 mmol) at 0° C. The reaction mixture was stirred at rt for4 h. Upon completion the product was extracted with ethyl acetate,washed with 1 molar HCl and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified directlywas purified on reverse phase HPLC.

Example 160

This example describes the synthesis of2-(5-(oxiran-2-yl)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid in an embodiment of the invention

To a stirring solution of ethyl2-(3-phenyl-4-(4-sulfamoylbenzyl)-5-vinyl-1H-pyrazol-1-yl)thiazole-4-carboxylate(0.1 g, 0.2 mmol) in ethyl acetate/acetone mixture was added a solutionof sodium bicarbonate (0.09 g, 1.0 mmol) in 2 mL of water followed byaddition of a solution of Oxone (0.373 g, 0.607 mmol) in 1 mL water. Thereaction mixture was stirred vigorously at rt for 3 days. Uponcompletion the product was extracted with ethyl acetate, washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude product was hydrolyzed with LiOH inTHF/MeOH/water then purified in HPLC without using any acid modifiers.

Example 161

This example describes the synthesis of2-(5-(oxiran-2-yl)-3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid in an embodiment of the invention

To a round bottom flask were added4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide (0.03 g, 0.09mmol) and DMF (0.5 ml), followed by NaH (3.6 mg, 0.09 mmol). Thereaction mixture was stirred at rt for 20 mins, at which time2,4-dibromothiazole (0.02 g, 0.09 mmol) was added. The reaction mixturewas heated to 100° C. for 1 h. Reaction was predominantly finished withno visible starting material this time. The reaction was quenched withwater and extracted with EtOAc and washed with water and brine, driedover Na₂SO₄, filtered, concentrated in vacuo. The residue was purifieddirectly on silica using gradient elution (20-80% ethyl acetate inhexanes over 12 CV) to afford the title compound.

Example 162

This example describes the synthesis of2-(3-(3-(tert-butylcarbamoyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(3-(3-(tert-butylcarbamoyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

To a mixture of ethyl2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(100.0 mg, 0.156 mmol), PdCl₂ (1.38 mg, 0.0078 mmol) and PPh₃ (4.0 mg,0.0156 mmol) in DMSO (1.8 mL) was added CsF (26.0 mg, 0.171 mmol) andwater (0.2 mL) successively. The reaction mixture was allowed to stirfor 5 min at rt, and tert-butyl isocyanide (26.4 μL, 0.234 mmol) wasadded. The reaction mixture was irradiated at 150° C. for 25 min in amicrowave reactor. The reaction mixture was poured into water andextracted with ethyl acetate (3×15 mL). The organic layers were washedwith brine (1×20 mL) and dried with anhydrous magnesium sulfate. Thecombined organic layer was concentrated in rotary evaporator and thecrude (43.0 mg) was used in the next step.

Step 2. Synthesis of2-(3-(3-(tert-butylcarbamoyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

Ethyl2-(3-(3-(tert-butylcarbamoyl)-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylatefrom Step 1 (43.0 mg, 0.065 mmol) was dissolved in a mixture of dioxaneand MeOH (1.0 mL/0.5 mL) and 1.0 mL of 1 N aqueous NaOH was added. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was neutralized by the addition of 1.0 M aqueous hydrochloricacid, diluted with ethyl acetate (15 mL), washed with water (10 mL), anddried with anhydrous magnesium sulfate. The organic layer wasconcentrated using a rotary evaporator and the residue was dissolved inDMSO and purified by HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradientfrom 40% to 100% CH₃CN for 4 min, 0.1% TFA) to give the title compound(11.0 mg, 26%). ¹H-NMR (MeOD) δ: 8.21 (s, 1H), 7.79-7.69 (m, 3H), 7.19(dd, J=8.6, 10.0 Hz, 1H), 7.11-7.05 (m, 2H), 4.21 (s, 2H), 3.28 (d,J=6.8 Hz, 2H), 1.44 (s, 9H), 1.18-1.10 (m, 1H), 0.43-0.39 (m, 2H),0.28-0.24 (m, 2H); MS (ES) 630.1 [M+H]⁺, LCMS RT=1.048 min.

Example 163

This example describes the synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicacid (Cpd. C) in an embodiment of the invention.

Step 1: Synthesis of Ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

To a solution of ethyl2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate(100.0 mg, 0.156 mmol) in CH₃CN (1.0 mL) and toluene (1.0 mL) were addedMo(CO)₆ (61.7 mg, 0.234 mmol), Pd(OAc)₂ (3.5 mg, 0.0156 mmol), T-BINAP(10.5 mg, 0.0156 mmol), Cs₂CO₃ (76.2 mg, 0.234 mmol) and pyrrolidine(20.0 μL, 0.234 mmol). The reaction mixture was heated at 90° C. for 16h. The reaction mixture was poured into water and extracted with ethylacetate (3×15 mL). The organic layers were washed with brine (1×20 mL)and dried with anhydrous magnesium sulfate. The combined organic layerwas concentrated in rotary evaporator and the crude (31.0 mg) was usedfor the next step.

Step 2: Synthesis of2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylicAcid

Ethyl2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylatefrom Step 1 (31.0 mg, 0.047 mmol) was dissolved in a mixture of dioxaneand MeOH (1.0 mL/0.5 mL) and 1.0 mL of 1 N aqueous NaOH was added. Thereaction mixture was stirred at room temperature 2 h. The reactionmixture was neutralized by addition of 1.0 M aqueous hydrochloric aciddiluted with ethyl acetate (15 mL), washed with water (10 mL), and driedwith anhydrous magnesium sulfate. The organic layer was concentratedusing a rotary evaporator, and the residue was dissolved in DMSO andpurified by HPLC (Phenomenex Gemini C18, H₂O/CH₃CN gradient from 40% to100% CH₃CN for 4 min, 0.1% TFA) to give the title compound (10.0 mg,24%). ¹H-NMR (MeOD) δ: 8.22 (s, 1H), 7.75-7.71 (m, 2H), 7.54 (dd, J=2.2,6.4 Hz, 1H), 7.24 (t, J=8.8 Hz, 1H), 7.07 (t, J=7.4 Hz, 2H), 4.20 (s,2H), 3.59 (t, J=7.1 Hz, 2H), 3.30 (d, J=6.9 Hz, 2H), 3.19 (t, J=2H),2.03-1.91 (m, 4H), 0.95-0.86 (m, 1H), 0.45-0.40 (m, 2H), 0.29-0.25 (m,2H); MS (ES) 628.0 [M+H]⁺, LCMS RT=0.968 min.

Example 164

This example describes the LDHA inhibitory activity, as measured by theassay set forth in Example 1, of exemplified compounds of formula (I) asembodiments. See Table 7. The compounds are assigned and activity levelbased on IC₅₀ as follows: +++<100 nM; ++100 nM-1000 nM; +>1000 nM-57000nM; and −>57000 nM.

TABLE 7 Inhibi- tory activity Cmpd Compound name IC₅₀ Example IDStructure and physical data (μM) Method  19

2-(3-phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.21 (s, 2H),7.80-7.71 (m, 2H), 7.72-7.63 (m, 2H), 7.52-7.37 (m, 5H), 7.28 (s, 2H),4.15 (s, 2H); MS (M + H)⁺ = 441 +++ 28  20

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s,1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.80- 7.74(m, 2H), 7.74- 7.67 (m, 2H), 7.57 (d, J = 7.6 Hz, 3H), 7.50-7.42 (m,4H), 7.37 (dd, J = 8.4, 6.3 Hz, 1H), 7.30 (s, 2H), 4.21 (s, 2H); MS (M +H)⁺ = 517 +++ 29  21

2-(3-([1,1′-biphenyl]- 3-yl)-4-bromo-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.93(s, 1H), 8.28 (s, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 7.7, 1.5Hz, 1H), 7.79 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (dd, J = 7.5, 1.7 Hz, 2H),7.63 (t, J = 7.8 + 30 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.40 (t, J =7.4 Hz, 1H); MS (M + H)⁺ = 427  22

2-(3-([1,1′-biphenyl]- 3-yl)-1H-pyrazol-1- yl)thiazole-4- carboxylicacid, TFA MS (M + H)⁺ = 348 + 31  23

2-(3-(3,4- difluorophenyl)-1H- pyrrolo[2,3- b]pyridin-1- yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 358 − 32  24

2-(5-hydroxy-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 459 ++ 33  25

2-(3-(3,4- difluorophenyl)-1H- pyrazolo[3,4- b]pyridin-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.88-8.78 (m,2H), 8.33 (s, 1H), 8.15 (ddd, J = 11.7, 7.7, 2.2 Hz, 1H), 8.05-7.97 (m,1H), 7.68 (dt, J = 10.8, 8.5 Hz, 1H), 7.60 (dd, J = 8.1,4.6 Hz, 1H); MS(M + H)⁺ = 359 − 34  26

2-(3-(4- sulfamoylbenzyl)- 1H-pyrrolo[2,3- b]pyridin-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 8.46 (dd, J =4.8, 1.5 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 7.8, 1.5 Hz, 1H), 8.07 (s,1H), 7.80-7.72 (m, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 7.9, 4.8Hz, 1H), 7.27 (s, 2H), 4.23 (s, 2H); MS (M + H)⁺ = 415 ++ 35  27

2-(4-(4-(methyl- sulfonyl)benzyl)- 3-phenyl-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.34 (s,1H), 8.23 (d, J = 1.1 Hz, 1H), 7.86-7.79 (m, 2H), 7.70-7.62 (m, 2H),7.53-7.37 (m, 5H), 4.19 (s, 2H), 3.17 (s, 3H); MS (M + H)⁺ = 440 − 36 28

2-(3-phenyl-4-(4- (trifluoromethyl) benzyl)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.33 (s,1H), 8.23 (s, 1H), 7.69- 7.59 (m, 4H), 7.50- 7.36 (m, 5H), 4.18 (s, 2H);MS (M + H)⁺ = 430 − 37  29

2-(3-([1,1′-biphenyl]- 3-yl)-1H-pyrrolo[2,3- b]pyridin-1- yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H), 8.68 (s,1H), 8.57 (d, J = 4.7 Hz, 1H), 8.55-8.50 (m, 1H), 8.28 (s, 1H), 8.07 (d,J = 2.0 Hz, 1H), 7.83 (m, 3H), 7.68 (d, J = 7.7 Hz, 1H), 7.61 (t, J =1.6 Hz, 1H), 7.54-7.44 (m, 3H), 7.43-7.35 (m, 1H); MS (M + H)⁺ = 398 −38  30

2-(5-(morpholine-4- carbonyl)-3-(4- sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s,1H), 8.40 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.73 (d, J =8.0 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.6Hz, 1H), 7.25 (s, 2H), 4.21 (s, 2H), 3.76-3.34 (m, 8H); MS (M + H)⁺ =527 + 39  31

2-(5-fluoro-3-(4- sulfamoylbenzyl)- 1H-indol-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.40 (dd, J =9.2, 4.5 Hz, 1H), 8.19 (d, J = 1.0 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J =8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 9.2, 2.6 Hz, 1H),7.27-7.18 (m, 3H), 4.16 (s, 2H); MS (M + H)⁺ = 432 ++ 40  32

2-(5-(morpholino- methyl)-3-(4- sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s,1H), 8.25 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.77 (s, 1H), 7.75- 7.69(m, 2H), 7.55- 7.49 (m, 2H), 7.45 (d, J = 1.8 Hz, 1H), 7.32 (dd, J =8.5, 1.6 Hz, 1H), 7.23 (s, 2H), 4.17 (s, 2H), 3.58- 3.46 (m, 6H), 2.35-2.23 (m, 4H); MS (M + H)⁺ = 513 + 41  33

2-(3-phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 8.71 (s, 1H),8.28 (s, 1H), 7.86- 7.81 (m, 2H), 7.81- 7.75 (m, 2H), 7.48- 7.35 (m,3H), 7.33- 7.29 (m, 2H), 7.27 (s, 2H); MS (M + H)⁺ = 443 +++ 42  34

2-(3-(4- sulfamoylbenzyl)- 1H-pyrrolo[3,2- c]pyridin-1- yl)thiazole-4-carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J = 1.0 Hz,1H), 8.46 (d, J = 5.8 Hz, 1H), 8.27 (s, 1H), 8.21 (dd, J = 5.8, 1.0 Hz,1H), 7.95 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H),7.23 (s, 2H), 4.25 (s, 2H) (acid OH not shown); MS (M + H)⁺ = 415 ++ 43 35

2-(3-(4- sulfamoylbenzyl)- 1H-indazol-1- yl)thiazole-4- carboxylic acid¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H),8.18 (s, 1H), 7.80 (dd, J = 8.0, 1.0 Hz, 1H), 7.77-7.72 (m, 2H), 7.67(ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.59-7.51 (m, 2H), 7.35 (ddd, J = 8.1,7.0, 0.9 Hz, 1H), 7.27 (s, 2H), 4.49 (s, 2H); MS (M + H)⁺ = 415 + 44  36

2-(3-(4- sulfamoylbenzyl)-5- ((tetrahydro-2H- pyran-4-yl)oxy)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ8.22 (d, J = 8.9 Hz, 1H), 8.04 (s, 1H), 7.74 (d, J = 3.6 Hz, 2H), 7.71(d, J = 1.9 Hz, 1H), 7.58- 7.50 (m, 2H), 7.23 (s, 2H), 7.06 (d, J = 2.4Hz, 1H), 7.01 (dd, J = 9.0, 2.4 Hz, 1H), 4.57-4.41 (m, 1H), 4.14 (s,2H), 3.83 (dt, J = 11.7, 4.4 Hz, 2H), ++ 3.44 (ddd, J = 11.8, 9.5, 2.8Hz, 2H), 1.90 (dd, J = 13.1, 3.5 Hz, 2H), 1.54 (ddd, J = 13.0, 8.8, 4.0Hz, 2H) (acid OH not shown); MS (M + H)⁺ = 514  37

2-(6-(morpholine-4- carbonyl)-3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole- 4-carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ8.45 (dd, J = 1.4, 0.7 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.75- 7.67(m, 2H), 7.58 (dd, J = 8.1, 0.7 Hz, 1H), 7.56-7.51 (m, 2H), 7.28-7.16(m, 3H), 4.19 (s, 2H), 3.54 (d, J = 41.1 Hz, 8H) (acid OH not shown); MS(M + H)⁺ = 527 + 46  38

2-(5-amino-3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid MS (M + H)⁺ = 492 +++ 12, 18  39

2-(3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.47 (d, J = 1.2 Hz, 1H), 7.87- 7.66(m, 2H), 7.69- 7.46 (m, 2H), 7.48- 7.19 (m, 5H), 4.24 (s, 2H); MS (M +H)⁺ = 545 +++ 14, 18  40

2-(3-([1,1′-biphenyl]- 3-yl)-5-amino-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.06 (s, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.79-7.74 (m, 2H), 7.70-7.62(m, 2H), 7.59-7.47 (m, 2H), 7.46-7.32 (m, 7H), 7.29 (s, 2H), 6.94 (s,2H), 4.05 (s, 2H); (M + H)⁺ = 532 +++ 12, 18  41

2-(3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),7.86-7.62 (m, 2H), 7.55 (q, J = 5.7, 4.9 Hz, 2H), 7.47- 7.38 (m, 2H),7.31 (s, 1H), 4.18 (s, 2H); (M + H)⁺ = 477 +++ 28  42

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H), 7.77 (tt,J = 6.6, 1.5 Hz, 3H), 7.67 (q, J = 1.6 Hz, 1H), 7.62-7.28 (m, 13H), 4.27(s, 2H); (M + H)⁺ = 589 +++ 14, 18  43

2-(3-(3,4- difluorophenyl)-5- iodo-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.23 (s,1H), 8.41 (d, J = 1.1 Hz, 1H), 7.83- 7.65 (m, 2H), 7.63- 7.47 (m, 2H),7.42- 7.35 (m, 1H), 7.32- 7.25 (m, 4H), 4.15 (s, 2H); (M + H)⁺ = 603 +++13, 18  44

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.27 (s, 1H), 8.46 (d, J = 0.9 Hz, 1H), 7.79-7.66 (m, 2H), 7.58-7.41(m, 5H), 7.30 (s, 3H), 7.33-7.26 (m, 1H), 4.23 (s, 2H); (M + H)⁺ = 509+++ 14, 18  45

2-(5-iodo-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.37 (d, J =1.2 Hz, 1H), 7.75- 7.67 (m, 2H), 7.57- 7.49 (m, 2H), 7.51- 7.36 (m, 3H),7.31- 7.24 (m, 4H), 4.12 (s, 2H); (M + H)⁺ = 567 +++ 13, 18  46

2-(5-cyclopropyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s,1H), 8.32 (s, 1H), 7.74-7.70 (m, 2H), 7.53-7.49 (m, 2H), 7.43-7.37 (m,3H), 7.31-7.26 (m, 4H), 4.14 (s, 2H), 2.25 (tt, J = 8.5, 5.6 Hz, 1H),1.02-0.92 (m, 2H), 0.71-0.62 (m, 2H); (M + H)⁺ = 481 +++ 112  47

2-(5-methyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.13 (s,1H), 8.29-8.19 (m, 1H), 7.78-7.65 (m, 2H), 7.53 (dq, J = 6.8, 1.3 Hz,2H), 7.49- 7.33 (m, 3H), 7.32-7.23 (m, 4H), 4.08 (s, 2H), 2.67 (d, J =1.1 Hz, 3H); (M + H)⁺ = 455 +++ 49  48

2-(3-phenyl-4- ((4-sulfamoyl- phenyl)amino)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.57 (s,1H), 8.25 (d, J = 2.4 Hz, 2H), 7.82 (dt, J = 8.1, 1.3 Hz, 3H), 7.55 (dd,J = 8.7, 1.2 Hz, 3H), 7.48-7.33 (m, 4H), 6.98 (s, 2H), 6.85- 6.76 (m,2H); (M + H)⁺ = 442 +++ 27  49

4-(((5-hydroxy-3- phenyl-1H-pyrazol-4- yl)methyl)amino)benzenesulfonamide (M + H)⁺ = 345 − 149  50

2-(5-carbamoyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 466 +++ 17, 18  51

2-(3-([1,1′-biphenyl]- 3-yl)-4-((4- sulfamoyl- phenyl)amino)-1H-pyrazol-l- yl)thiazole-4- carboxylic acid. (M + H)⁺ = 518 +++ 27  52

2-(3-([1,1′-biphenyl]- 3-yl)-5-cyclopropyl-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.12 (s, 1H), 7.80-7.73 (m, 2H), 7.73-7.59 (m, 2H), 7.60-7.47 (m, 2H),7.42 (d, J = 4.3 Hz, 4H), 7.43-7.28 (m, 5H), 4.19 (s, 2H), 2.30 (tt, J =8.6, 5.6 Hz, 1H), 1.04-0.95 (m, 2H), 0.73-0.64 (m, 2H); (M + H)⁺ = 557+++ 112  53

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 493 ++ 147  54

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 533 ++ 147  55

2-(3-(2′-fluoro-[1,1′- biphenyl]-3-yl)-5- hydroxy-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺= 551 ++ 147  56

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- amino-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 560 + 12, 18  57

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)-5-methylthiazole-4- carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s,1H), 7.81-7.65 (m, 2H), 7.48 (dq, J = 6.8, 1.3 Hz, 2H), 7.49- 7.26 (m,5H), 7.24 (s, 2H), 6.82 (s, 2H), 3.97 (s, 2H), 2.68 (d, J = 1.2 Hz, 3H),2.52 (d, J = 1.2 Hz, 1H); (M + H)⁺ = 470 ++ 148  58

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 484 + 12  59

2-(5-(cyanomethyl)- 3-phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.70-7.63 (m, 2H), 7.59-7.49 (m, 2H), 7.46-7.34 (m, 3H), 7.30-7.22 (m,4H), 4.67 (s, 2H), 4.22 (s, 2H); (M + H)⁺ = 480 ++ 19, 20  60

2-(3-(3,4- difluorophenyl)-5- methoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 507 ++ 73  61

2-(3-(3,4- difluorophenyl)-5- ethoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid ++ 73  62

2-(3-phenyl-5- (trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid (M + H)⁺ = 340 + 150  63

2-(3-(2′-fluoro-[1,1′- biphenyl]-3-yl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 382 − 147  64

2-(3-(3,4- difluorophenyl)-5- (hydroxymethyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid. (M + H)⁺ = 338 − 151  65

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid − 147  66

2-(5-hydroxy-3- methyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147  67

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- carbamoylbenzyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147  68

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- carboxybenzyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147  69

2-(3-(3- bromophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid + 147  70

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxamide − 152  71

2-(5-carboxy-3-(3,4- difluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid − 151  72

4-((1-(4-(1H-tetrazol- 5-yl)thiazol-2-yl)-3- ([1,1′-biphenyl]-3-yl)-5-hydroxy-1H- pyrazol-4- yl)methyl)benzene- sulfonamide + 153  73

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate + 147  74

2-(5-(cyanomethyl)- 3-(3,4- difluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid + 19, 20  75

2-(5-((1H-tetrazol-5- yl)methyl)-3-(3,4- difluorophenyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid + 21, 20  76

2-(3-phenyl-4-(4- sulfamoylphenyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 427 + 69  77

ethyl 2-(3-phenyl-4- (4-sulfamoylbenzyl)- 5-(trifluoromethyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 537 + 14  78

2-(5-iodo-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxamide + 152  79

2-(3-phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxamide + 152  80

2-(3-phenyl-5- (pyridin-3-ylamino)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 533 + 154  81

2-(5-hydroxy-3- (naphthalen-1-yl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid + 69  82

2-(5-hydroxy-3- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid + 147  83

4-((5-amino-1-(6- chloropyridazin-3- yl)-3-phenyl-1H- pyrazol-4-yl)methyl)benzene- sulfonamide + 148  84

4-((5-amino-1-(3- methylbenzoyl)-3- phenyl-1H-pyrazol-4-yl)methyl)benzene- sulfonamide + 148  85

4-((5-amino-1-(3- fluorobenzoyl)-3- phenyl-1H-pyrazol-4-yl)methyl)benzene- sulfonamide + 148  86

4-((5-amino-1-(4- methylthiazol-2-yl)- 3-phenyl-1H-pyrazol-4-yl)methyl)benzene- sulfonamide + 148  87

2-(5-((1H-tetrazol-5- yl)methyl)-3-phenyl- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 523 + 21, 18  88

4-((1-(4-(hydroxy- methyl)thiazol-2- yl)-3-phenyl-5-(trifluoromethyl)-1H- pyrazol-4- yl)methyl)benzene- sulfonamide + 22  89

2-(3-(6- fluoronaphthalen-1- yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid − 69  90

2-(3-phenyl-4-((4- sulfamoylpiperazin- 1-yl)methyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 449 + 155  91

2-(5-hydroxy-3- phenyl-1H-pyrazol-1- yl)thiazole-4- carboxylic acid −147  92

2-(5-hydroxy-3-(3- (methylsulfonyl) phenyl)-1H- pyrazol-1-yl)thiazole-4- carboxylic acid − 147  93

2-(5-hydroxy-3-(3- morpholinophenyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid − 147  94

2-(3-(4-fluoro-3- (methylsulfonyl) phenyl)-5-hydroxy- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147  95

2-(3-(3,5- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147  96

2-(3-(2,3- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147  97

2-(3-(2,4- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147  98

1-((ethoxy- carbonyl)oxy)ethyl 2-(3-(3,4- difluorophenyl)-5-(1-((ethoxy- carbonyl)oxy)ethoxy)- 1H-pyrazol- 1-yl)thiazole-4-carboxylate − 156  99

(pivaloyloxy)methyl 2-(3-(4- fluorophenyl)-5- ((pivaloyloxy)methoxy)-1H-pyrazol-1- yl)thiazole-4- carboxylate − 156 100

2-(3-(2,6- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 101

3-(3-fluoro-4- (methylsulfonyl)phenyl)- 1-(4- (hydroxymethyl)thiazol-2-yl)-1H-pyrazol- 5-ol − 147 102

2-(3-(2,5- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 103

2-(3-(4-fluoro-3- (methylsulfonamido) phenyl)-5-hydroxy- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 104

2-(3-(3-benzyl-4- fluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 105

1-((ethoxy- carbonyl)oxy)ethyl 2-(3-(3,4-difluoro- phenyl)-5-hydroxy-1H-pyrazol-1- yl)thiazole-4- carboxylate − 156 106

2-morpholinoethyl 2- (3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylate − 156 107

2,3-dihydro-1H- inden-5-yl 2-(3-(3,4- difluorophenyl)-5-((dimethylcarbamoyl) oxy)-1H-pyrazol-1- yl)thiazole-4- carboxylate − 156108

2,3-dihydro-1H- inden-5-yl 2-(3-(3,4- difluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylate − 156 109

(isobutyryloxy)methyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylate − 156 110

2-(3-(3-(N- benzylsulfamoyl)-4- fluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 111

2-(3-(4-(cyclopropane- sulfonamido)-3- fluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147 112

2-(3-(4-(2- (cyclopropane- sulfonamido)ethyl)-3- fluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147 113

2-(4-benzyl-3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 114

2-(3-(4-fluoro-3-(N- methylsulfamoyl) phenyl)-5-hydroxy-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid − 147 115

methyl 2-(3,4- difluorophenyl)-5- oxo-4,5- dihydropyrazolo[1,5-a]thieno[3,2- e]pyrimidine-6- carboxylate (M + H)⁺ = 362 − 157 116

2-(3,4- difluorophenyl)-5- oxo-4,5- dihydropyrazolo[1,5- a]thieno[3,2-e]pyrimidine-6- carboxylic acid (M + H)⁺ = 348 − 157 117

tert-butyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(3- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate − 69 118

tert-butyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-4-phenyl- 1H-pyrazol-1-yl)thiazole-4- carboxylate − 69 119

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indazol- 1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 374 − 69 120

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indazol- 1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 352 − 34 121

ethyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylate (M + H)⁺ = 352 − 147 122

2-(3-(4-fluoro-3-(2- (methylsulfonamido) ethyl)phenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 427 −147 123

ethyl 2-(5-amino-3- (3,4-difluorophenyl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 520 + 12 124

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- (N-methyl-sulfamoyl)benzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺= 547 − 69 125

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 373 − 32 126

2-(4-acetamido-5- hydroxy-3-phenyl- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 345 − 33 127

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)thiazole- 4-carboxamide − 152 128

4-((5-amino-1-(6- oxo-1,6- dihydropyridazin-3- yl)-3-phenyl-1H-pyrazol-4- yl)methyl)benzene- sulfonamide − 148 129

ethyl 3-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)benzoate − 148 130

3-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)benzoicacid − 148 131

4-((5-amino-1-(4- (hydroxymethyl) thiazol-2-yl)-3-phenyl- 1H-pyrazol-4-yl)methyl)benzene- sulfonamide − 148 132

4-((5-((1H-tetrazol-5- yl)methyl)-1-(4- (hydroxymethyl)thiazol-2-yl)-3-phenyl- 1H-pyrazol-4- yl)methyl)benzene- sulfonamide(M + H)⁺ = 509 − 22 133

methyl)-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylate (M + H)⁺ = 537 − 21 134

ethyl 2-(5-((1H- tetrazol-5-yl)methyl)- 3-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 551 − 21 135

ethyl 2-(5- (cyanomethyl)-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 508 − 19 136

2-(3-phenyl-4-(4- sulfamoylbenzamido)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 449 − 158 137

4-((5-amino-3- phenyl-1-(4- (trifluoromethyl) thiazol-2-yl)-1H-pyrazol-4- yl)methyl)benzene- sulfonamide − 148 138

2-(3-phenyl-4- ((piperazine-1- sulfonamido)methyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 449 − 155 139

2-(3-phenyl-4-(((4- sulfamoylphenyl) amino)methyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 456 − 155 140

ethyl 6-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)pyridazine-3- carboxylate − 148 141

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ =585 − 14 142

2-(3-phenyl-4-((4- sulfamoylbenzyl) amino)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 456 − 158 143

4-((5-amino-1-(5- amino-1-methyl-1H- pyrazole-4-carbonyl)-3-phenyl-1H-pyrazol- 4-yl)methyl)benzene- sulfonamide − 148 144

6-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)picolinicacid + 148 145

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)isonicotinic acid − 148 146

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)-5-methylthiazole-4- carboxylate (M + H)⁺ = 498 − 148 147

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)-5-methylthiazole-4- carboxylic acid (M + H)⁺ = 470 + 148 148

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 456 + 148 149

(5-methyl-2-oxo-1,3- dioxol-4-yl)methyl 2- (3-phenyl-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylate ++ 156 150

4-((5-amino-1-(1H- indole-7-carbonyl)-3- phenyl-1H-pyrazol-4-yl)methyl)benzene- sulfonamide − 148 151

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)oxazole-4- carboxylate (M + H)⁺ = 468 + 148 152

4-((5-amino-1-(4- hydroxypyrimidin-2- yl)-3-phenyl-1H- pyrazol-4-yl)methyl)benzene- sulfonamide − 148 153

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)oxazole-4-carboxylic acid (M + H)⁺ = 440 ++ 148 154

4-((3-phenyl-1-(4- (2,2,2-trifluoro-1- hydroxyethyl)thiazol-2-yl)-1H-pyrazol-4- yl)methyl)benzene- sulfonamide 1H NMR (400 MHz,DMSO-d6) δ 8.21 (d, J = 0.8 Hz, 1H), 7.76- 7.61 (m, 4H), 7.57 (d, J =0.7 Hz, 1H), 7.49-7.35 (m, 5H), 7.26 (s, 2H), 6.99 (d, J = 6.3 Hz, 1H),5.27- 5.15 (m, 1H), 4.14 (s, 2H); (M + H)⁺ = 495 ++ 159 155

2-(3,5-diphenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.23 (s, 1H),7.75-7.67 (m, 0H), 7.66-7.55 (m, 4H), 7.40 (s, 4H), 7.47- 7.30 (m, 4H),7.30- 7.15 (m, 5H), 3.98 (s, 2H); (M + H)⁺ = 517 +++ 15 156

2-(3-phenyl-5- (pyridin-4-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s,1H), 8.64-8.57 (m, 2H), 8.23 (s, 1H), 7.66- 7.54 (m, 4H), 7.47-7.34 (m,5H), 7.25-7.16 (m, 4H), 4.05 (q, J = 5.2 Hz, 1H), 4.01 (s, 2H), + 153.14 (d, J = 5.2 Hz, 2H); (M + H)⁺ = 518 157

2-(3-phenyl-5- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 8.71- 8.61(m, 2H), 8.22 (s, 1H), 8.00 (ddd, J = 7.9, 2.2, 1.7 Hz, 1H), 7.66-7.57(m, 4H), 7.52 (ddd, J = 7.9, 5.0, 0.9 Hz, 1H), 7.47-7.34 ++ 15 (m, 3H),7.25-7.17 (m, 4H), 4.01 (s, 2H); (M + H)⁺ = 518 158

2-(3-isopropyl-5- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 483 + 49 159

2-(5-isopropyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (600 MHz, DMSO-d6) δ 13.14 (s,1H), 8.28 (s, 1H), 7.74-7.68 (m, 2H), 7.51-7.45 (m, 2H), 7.42-7.34 (m,3H), 7.31-7.25 (m, 4H), 4.21-4.12 (m, 1H), 4.15 (s, 2H), 1.28- 1.24 (m,6H); (M + H)⁺ = 483 ++ 49 160

2-(5- (cyclopropylethynyl)- 3-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.13 (s, 1H), 8.31 (s, 1H), 7.76-7.68 (m, 2H), 7.65-7.55 (m, 2H),7.50-7.37 (m, 3H), 7.36-7.21 (m, 4H), 4.17 (s, 2H), 1.60 (tt, J = 7.7,5.3 Hz, 1H), 1.00-0.86 (m, 4H); (M + H)⁺ = 505 +++ 16 161

4-((3-([1,1′- biphenyl]-3-yl)-1H- pyrazol-4- yl)amino)benzene-sulfonamide (M + H)⁺ = 391 − 25 162

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-4-((4- sulfamoylphenyl)amino)-1H-pyrazol- 1-yl)thiazole-4- carboxylate (M + H)⁺ = 546 + 26 163

ethyl 2-(3- cyclopropyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 511 − 33 164

ethyl 2-(5- cyclopropyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 511 + 33 165

cyclopropyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 483 + 33 166

2-(5-cyclopropyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s,1H), 8.35 (s, 1H), 7.83-7.71 (m, 4H), 7.45-7.31 (m, 3H), 7.29-7.15 (m,4H), 3.31 (s, 2H), 2.63 (tt, J = 8.5, 5.5 Hz, 1H), 0.99-0.80 (m, 4H);(M + H)⁺ = 483 +++ 33 167

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- vinyl-1H-pyrazol-1- yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.32 (s, 1H),7.80-7.72 (m, 2H), 7.65 (dd, J = 18.1, 11.9 Hz, 1H), 7.59- 7.50 (m, 2H),7.55- 7.26 (m, 8H), 5.63- 5.54 (m, 1H), 5.45 (dd, J = 18.1, 1.1 Hz, 1H),4.21 (s, 2H); (M + H)⁺ = 467 +++ 15 168

ethyl 2-(3- cyclopentyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 539 − 33 169

ethyl 2-(5- cyclopentyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 539 − 33 170

2-(3-cyclopentyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 511 + 33 171

2-(5-cyclopentyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 511 ++ 33 172

2-(3-cyclohexyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 525 + 33 173

2-(5-cyclohexyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 525 + 33 174

2-(3-cyclopentyl-5- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 508 + 49 175

2-(5-cyclopentyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 508 ++ 49 176

2-(3-cyclohexyl-5- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 523 + 49 177

2-(5-cyclohexyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 523 + 49 178

2-(5-(oxiran-2-yl)-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 483 + 160 179

2-(3-phenyl-5- (phenylethynyl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 541 + 16 180

ethyl 2-(5-([1,1′- biphenyl]-3-yl)-3- cyclopropyl-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ =585 − 49 181

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- cyclopropyl-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylate 1H NMR (400MHz, DMSO-d6) δ 8.40 (s, 1H), 7.80-7.73 (m, 2H), 7.73-7.47 (m, 4H),7.47- 7.28 (m, 9H), 4.33 (q, J = 7.1 Hz, 2H), 4.20 (s, 2H), 3.35-3.25(m, 1H), 2.25 (tt, J = 8.5, 5.6 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H),1.06-0.96 (m, 2H), 0.75-0.65 (m, 2H); (M + H)⁺ = 585 − 49 182

cyclopropyl-4-(2- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 575 + 49 183

2-(3-([1,1′-biphenyl]-3- yl)-5-cyclopropyl-4-(2- fluoro-4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz,DMSO-d6) δ 13.11 (s, 1H), 8.34 (s, 1H), 7.70 (dt, J = 6.6, 2.1 Hz, 1H),7.62 (dt, J = 2.7, 1.4 Hz, 2H), 7.61-7.49 (m, 4H), 7.49- 7.40 (m, 6H),7.39-7.33 (m, 1H), 7.28-7.19 (m, 1H), 4.14 (s, 2H), 2.24 (tt, J = 8.5,5.6 Hz, 1H), 1.13-0.90 (m, 2H), 0.78- 0.60 (m, 2H); (M + H)⁺ = 575 +++49 184

2-(5-([1,1′-biphenyl]- 3-yl)-3-cyclopropyl- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 557 + 49 185

2-(5-benzyl-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s,1H), 7.66-7.53 (m, 4H), 7.45-7.33 (m, 3H), 7.28-7.06 (m, 10H), 4.69 (s,2H), 4.18 (s, 2H), 4.11-4.03 (m, 1H), 3.17 (d, J = 4.6 Hz, 2H); (M + H)⁺= 531 ++ 49 186

2-(5-([1,1-biphenyl]- 3-yl)-3-cyclopropyl- 4-(4- sulfamoylphenoxy)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 559 + 33 187

2-(3-([1,1-biphenyl]- 3-yl)-5-cyclopropyl- 4-(4-sulfamoylphenoxy)-1H-pyrazol-1-yl) thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.17 (s, 1H), 8.36 (s, 1H), 7.93 (td, J = 1.8,0.5 Hz, 1H), 7.85- 7.71(m, 3H), 7.66 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.56-7.32 (m, 6H), 7.30-7.21 (m, 4H), 2.73-2.61 (m, 1H), 1.02-0.90 (m, 2H), 0.93-0.83 (m, 2H);(M + H)⁺ = 559 +++ 33 188

2-(3- (cyclopropylmethyl)- 5-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 495 ++ 141 189

2-(5- (cyclopropylmethyl)- 3-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 495 +++ 141 190

methyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)-4-(trifluoromethyl) pyrimidine-5- carboxylate − 148 191

6-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)pyridazine-3- carboxylic acid − 148 192

2-(6- (morpholinomethyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4-carboxylic acid, NH3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H),7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.56-7.50 (m, 2H), 7.50-7.46 (m, 1H),7.45 (s, 1H), 7.23 (s, 2H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 4.15 (s,2H), 3.55 (dd, J = 8.9, 4.4 Hz, 6H), 2.34 (t, J = 4.6 Hz, 4H) (acid OHnot shown); MS (M + H)⁺ = 513 ++ 41 193

2-(4-(morpholinomethyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4-carboxylic acid, NH3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J = 8.4 Hz,1H), 7.79-7.70 (m, 2H), 7.48 (s, 1H), 7.46 (s, 1H), 7.41-7.34 (m, 2H),7.31-7.23 (m, 3H), 7.06 (dd, J = 7.3, 1.0 Hz, 1H), 4.51 (s, 2H), 3.51(dd, J = 9.5, 4.9 Hz, 6H), 2.35-2.21 (m, 4H) (acid OH not shown); MS(M + H)⁺ = 513 ++ 41 194

2-(5-(2-fluorobenzyl)- 3-(4-sulfamoyl- benzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH3 ¹H NMR (400 MHz, DMSO-d₆) δ8.23-8.17 (m, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.73-7.67 (m, 2H),7.52-7.45 (m, 2H), 7.42 (d, J = 1.6 Hz, 1H), 7.23 (m, 5H), 7.17-7.05 (m,2H), 4.12 (s, 2H), 4.02 (s, 2H) (acid OH not shown); MS (M + H)⁺ = 522++ 40 195

2-(5-(2-fluorophenyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 8.42 (dd, J= 8.6, 0.6 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.77- 7.68 (m, 3H),7.59-7.54 (m, 3H), 7.52 (td, J = 7.8, 1.7 Hz, 1H), 7.39 (tdd, J = 7.8,5.1, 1.8 Hz, 1H), 7.33-7.24 (m, 2H), 7.21 (s, 2H), 4.22 (s, 2H); MS (M +H)⁺ = 508 +++ 40 196

2-(3-(4- sulfamoylbenzyl)- 1H-indol-1- yl)thiazole-4- carboxylic acid ¹HNMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 8.34 (dt, J = 8.4, 0.9 Hz, 1H),8.18 (s, 1H), 7.83 (s, 1H), 7.75-7.67 (m, 2H), 7.57-7.48 (m,3H), 7.37(ddd, J = 8.4, 7.1, 1.2 Hz, 1H), 7.22 (s, 2H), 7.21-7.16 (m, 1H), 4.18(s, 2H); MS (M + H)⁺ = 414 ++ 40 197

2-(3-(4- sulfamoylbenzyl)-6- (trifluoromethyl)-1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.20(s, 1H), 8.79 (dd, J = 1.7, 0.9 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H),7.78-7.68 (m, 3H), 7.59-7.49 (m, 3H), 7.23 (s, 2H), 4.23 (s, 2H); MS(M + H)⁺ = 482 ++ 40 198

2-(4-(2-fluorobenzyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.34 (dd, J= 8.4, 0.9 Hz, 1H), 8.18 (s, 1H), 7.75-7.70 (m, 2H), 7.69 (s, 1H),7.35-7.21 (m, 6H), 7.17 (ddd, J = 9.6, 8.2, 1.3 Hz, 1H), 7.04 (td, J =7.4, 1.3 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.78-6.71 (m, 1H), 4.17 (s,2H), 4.14 (s, 2H); MS (M + H)⁺ = 522 ++ 40 199

2-(4-(4-(hydroxy- methyl)benzyl)-3- phenyl-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.20 (s, 1H),8.11 (s, 1H), 7.73- 7.65 (m, 2H), 7.50- 7.36 (m, 3H), 7.27- 7.15 (m,4H), 5.07 (t, J = 5.8 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 4.02 (s, 2H);MS (M + H)⁺ = 392 − 28 200

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4-(hydroxy- methyl)benzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ13.16 (s, 1H), 8.21 (d, J = 2.9 Hz, 2H), 7.83 (t, J = 1.8 Hz, 1H), 7.70(ddt, J = 7.7, 6.0, 1.4 Hz, 2H), 7.61-7.49 (m, 3H), 7.44 (s, 1H),7.45-7.31 (m, 2H), 7.29-7.17 (m, 4H), 5.09 (t, J = 5.8 Hz, + 29 1H),4.45 (d, J = 5.3 Hz, 2H), 4.09 (s, 2H); MS (M + H)⁺ = 468 201

2-(6-(hydroxymethyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 8.27-8.23(m, 1H), 8.19 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.74- 7.69 (m, 2H),7.55-7.49 (m, 2H), 7.49-7.43 (m, 1H), 7.22 (s, 2H), 7.15 (dd, J = 8.1,1.4 Hz, 1H), 5.22 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 4.6 Hz, 2H), 4.16(s, 2H); MS (M + H)⁺ = 444 ++ 40 202

2-(7-fluoro-3-(4- sulfamoylbenzyl)- 1H-indol-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.37 (s, 1H),7.72 (m, 3H), 7.52 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.24(s, 2H), 7.21- 7.07 (m, 2H), 4.17 (s, 2H); MS (M + H)⁺ = 432 ++ 40 203

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2- cyclopropylethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 +++ 49 204

2-(5-([1,1′-biphenyl]- 3-yl)-3-(2- cyclopropylethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 + 49 205

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2,2-difluoro- cyclopropyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR(400 MHz, DMSO-d6) δ 13.29- 12.98 (m, 1H), 8.34 (s, 1H), 7.78-7.73 (m,2H), 7.73-7.66 (m, 2H), 7.63-7.49 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.32(m, 3H), 7.30 (s, 2H), 4.22 (s, 2H), 3.30-3.24 +++ 49 (m, 1H), 2.24-1.98(m, 1H), 1.81-1.60 (m, 1H); (M + H)⁺ = 593 206

2-(5-([1,1′-biphenyl]- 3-yl)-3-(2,2- difluorocyclopropyl)- 4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺= 593 + 49 207

2-(3-([1,1′-biphenyl]-3- yl)-5-((2,2-difluoro- cyclopropyl)methyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR(400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.30 (s, 1H), 7.77- 7.67 (m, 4H),7.61 (dt, J = 7.8, 1.4 Hz, 1H), 7.52 (td, J = 7.6, 0.8 Hz, 1H),7.48-7.40 (m, 4H), 7.38-7.33 (m, 3H), 7.30 (s, 2H), 4.19 (s, 2H), 3.40(td, J = 19.2, 17.2, 7.3 Hz, 2H), 2.28-2.11 (m, 1H), 1.55-1.32 (m, 1H);(M + H)⁺ = 607 +++ 49 208

2-(5-([1,1′-biphenyl]- 3-yl)-3-((2,2- difluorocyclopropyl) methyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺= 607 + 49 209

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2- cyclopropylethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 +++ 49 210

4-((1-(4-oxo-3,4- dihydrothieno[3,2- d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4- yl)methyl)benzene- sulfonamide ¹H NMR (400 MHz,DMSO-d6) δ 12.79 (s, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H),7.74-7.68 (m, 2H), 7.68-7.62 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.34 (m,3H), 7.25 (s, 2H), 4.16 (s, 2H); MS (M + H)⁺ = 464 − 51 211

4-((1-(4- aminothieno[3,2- d]pyrimidin-7-yl)-3- phenyl-1H-pyrazol-4-yl)methyl)benzene- sulfonamide, TFA ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (d,J = 4.9 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H),7.87 (s, 2H), 7.69 (m, 4H), 7.49- 7.30 (m, 5H), 7.26 (s, 2H), 4.17 (s,2H); MS (M + H)⁺ = 463 + 52 212

1-methyl-2-(3- phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)-1H-imidazole-5- carboxylic acid, TFA; MS (M + H)⁺ = 438 − 53 213

5-(3-phenyl-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiophene-3-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.45 (s,1H), 7.96 (d, J = 1.6 Hz, 1H), 7.73-7.66 (m, 2H), 7.63-7.55 (m, 3H),7.44-7.32 (m, 5H), 7.26 (s, 2H), 4.08 (s, 2H); MS (M + H)⁺ = 440 + 54214

2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- (1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2- fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 13.15(s, 1H), 8.29 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.78-7.72 (m, 2H), 7.52(dd, J = 9.6, 1.8 Hz, 1H), 7.46 (dd, J = 8.0, 1.8 Hz, 1H), 7.40 (s, 2H),7.34 (ddd, J = 8.5, 5.0, 2.2 Hz, 1H), 7.26 (dd, J = 11.0, 8.5 Hz, 1H),7.12 (t, J = 7.8 Hz, 1H), 4.10 (s, 2H), 3.85 (s, 3H), 3.15 (d, J = 7.0Hz, 2H), 1.14-1.01 +++ 55 (m, 1H), 0.37-0.14 (m, 4H); MS (M + H)⁺ = 611215

2-(5- (cyclopropylmethyl)- 3-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(2-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 626 +++ 56 216

2-(3- (cyclopropylmethyl)- 5-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(2-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 626 − 56 217

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(1- methyl-1H-pyrazol-4-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 611 +++ 57 218

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(1- methyl-1H-pyrazol-4-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 611 − 57 219

2-(5- (cyclopropylmethyl)- 3-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 626 +++ 58 220

2-(3- (cyclopropylmethyl)- 5-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 626 − 58 221

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 +++ 59 222

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 − 59 223

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 +++ 60 224

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 − 60 225

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 NA 61 226

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 − 61 227

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(5-methyl-thiophen-2-yl)phenyl)-4- (3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 NMR (HCl salt)from YSM14-67 ¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H),7.67 (t, J = 7.9 Hz, 1H), 7.62 (dd, J = 7.6, 2.2 Hz, 1H), 7.58 (s, 2H),7.50 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.34 (dd, J = 11.3, 8.6 Hz, 1H),7.19 (dd, J = 11.3, 1.6 Hz, 1H), 7.13 (dd, J = 3.6, 0.9 Hz, 1H), 7.06(dd, J = 8.1, 1.6 +++ 62 Hz, 1H), 6.81 (dt, J = 3.6, 1.1 Hz, 1H), 4.14(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.44 (d, J = 1.1 Hz, 3H), 1.19-1.03(m, 1H), 0.39-0.28 (m, 2H), 0.24-0.14 (m, 2H) 228

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 627 − 62 229

ethyl 2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- (5-methylthiophen-2-yl)phenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylate ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.55 (dd, J = 7.4, 2.2 Hz, 1H), 7.37 (ddd, J = 8.5, 4.7,2.2 Hz, 1H), 7.15-7.04 (m, 3H), 7.00 (dd, J = 11.1, 1.6 Hz, 1H), 6.73(dt, J = 3.7, 1.0 Hz, 1H), 4.93 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.07(s, 2H), 3.21 (d, J = 6.8 Hz, 2H), 2.49 (d, J = 1.1 Hz, 3H), 1.41 (t, J= 7.1 Hz, 3H), 1.19-1.06 (m, − 63 1H), 0.49-0.38 (m, 2H), 0.28 (dt, J =6.1, 4.7 Hz, 2H); MS (M + H)⁺ = 655 230

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(5-methyl-furan-2-yl)phenyl)-4-(3- fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ13.10 (s, 1H), 8.29 (s, 1H), 7.76 (dd, J = 7.4, 2.3 Hz, 1H), 7.67 (t, J= 7.9 Hz, 1H), 7.57 (s, 2H), 7.54 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H), 7.33(dd, J = 11.2, 8.6 Hz, 1H), 7.20 (dd, J = 11.3, 1.6 Hz, 1H), 7.07 (dd, J= 8.1, 1.6 Hz, 1H), 6.70 (t, J = 3.5 Hz, 1H), 6.22 (dt, J = 3.1, 1.0 Hz,1H), 4.15 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.17-1.06 (m,1H), 0.38-0.28 (m, 2H), 0.24-0.14 (m, 2H); MS (M + H)⁺ = 611 +++ 64 231

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(5-methyl-thiazol-2-yl)phenyl)-4- (3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 13.13(s, 1H), 8.30 (dd, J = 7.2, 2.3 Hz, 1H), 8.28 (s, 1H), 7.70-7.59 (m,3H), 7.54 (s, 2H), 7.43 (dd, J = 11.1, 8.7 Hz, 1H), 7.16 (dd, J = 11.4,1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.14 (s, 2H), 3.19- 3.14(m, 2H), 2.49 (d, J = 1.2 Hz, 3H), 1.18-1.05 (m, 1H), 0.39-0.29 (m, 2H),0.24-0.15 (m, 2H); MS (M + H)⁺ = 628 +++ 65 232

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(2-methyl-thiazol-5-yl)phenyl)-4-(3- fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ13.13 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.68 (dd, J = 7.4, 2.0 Hz,1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57 (m, 3H), 7.39 (dd, J = 10.8, 8.7 Hz,1H), 7.17 (d, J = 11.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.15 (s, 2H),3.16 (d, J = 6.9 Hz, 2H), 2.66 (s, 3H), 1.18-1.01 (m, 1H), 0.37- 0.27(m, 2H), 0.21 (d, J = 4.9 Hz, 2H); MS (M + H)⁺ = 628 +++ 66 233

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(5-methyl-thiophen-2-yl)phenyl)-4- (2-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s,1H), 8.29 (s, 1H), 7.63 (dd, J = 7.5, 2.2 Hz, 1H), 7.56 (dd, J = 9.6,1.8 Hz, 1H), 7.53- 7.49 (m, 1H), 7.49-7.44 (m, 1H), 7.42 (s, 2H), 7.34(dd, J = 11.3, 8.6 Hz, 1H), 7.19- 7.11 (m, 2H), 6.81 (dt, J = 3.6, 1.1Hz, 1H), 4.08 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.44 (d, J = 1.1 Hz,3H), 1.17-1.02 (m, 1H), 0.35-0.27 (m, 2H), 0.22- 0.14 (m, 2H); MS (M +H)⁺ = 627 +++ 67 234

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (thiophen-2- yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylicacid, TFA; MS (M + H)⁺ = 613 +++ 68 235

¹H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 0.8 Hz, 1H), 7.74-7.68 (m, 2H),7.67-7.63 (m, 2H), 7.62 (s, 1H), 7.47- 7.41 (m, 2H), 7.41-7.37 (m, 2H),7.26 (s, 2H), 4.13 (s, 2H); (M + H)⁺ = 476.4 + 161 236

(M + H)⁺ = 619.7 − 141 237

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.71-7.64 (m,2H),7.63-7.55 (m, 2H), 7.37-7.23 (m, 6H), 6.99 (dt, J = 2.9, 1.6 Hz,1H), 6.95 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.89 (dtd, J = 7.6, 1.6, 0.9Hz, 1H), 4.14 (s, 2H), 3.75 (s, 3H), 3.13 (d, J = 6.9 Hz, 2H), 1.17-1.04(m, 1H), 0.36-0.27 (m, 2H), 0.22-0.15 (m, 2H); (M + H)⁺ = 619.7 +++ 141238

(M + H)⁺ = 607.7 + 141 239

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.73-7.68 (m,2H), 7.68-7.64 (m, 1H), 7.62 (dd, J = 7.6, 2.3 Hz, 1H), 7.54-7.46 (m,1H), 7.39 (dd, J = 10.8, 8.6 Hz, 1H), 7.35 (dd, J = 2.7, 1.4 Hz, 0H),7.34-7.27 (m, 5H), 7.26-7.22 (m, 1H), 7.18 (dq, J = 7.8, 1.3 Hz, 1H),4.18 (s, 2H), 3.17 (d, J = 6.9 Hz, 2H), 1.14 (ddd, J = 12.8, 7.7, 4.9Hz, 0H), 0.45-0.27 (m, 2H), 0.28- 0.14 (m, 2H); (M + H)⁺ = 607.7 +++ 141240

¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.46 (s, 1H), 7.80-7.72 (m,2H), 7.59 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.56 (dd, J = 7.5, 2.3 Hz,1H), 7.50-7.43 (m, 3H), 7.36-7.25 (m, 6H), 4.27 (s, 2H); (M + H)⁺ =621.6 +++ 14 241

¹H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.44 (s, 1H), 7.75-7.69 (m,2H), 7.62 (dd, J = 7.5, 2.3 Hz, 1H), 7.58 (ddd, J = 8.5, 4.8, 2.3 Hz,1H), 7.51-7.42 (m, 2H), 7.39-7.33 (m, 1H), 7.32-7.26 (m, 4H), 7.27-7.20(m, 2H), 4.25 (s, 2H); (M + H)⁺ = 621.6 +++ 14 242

¹H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.45 (s, 1H), 7.78-7.72 (m,2H), 7.63 (dd, J = 7.5, 2.3 Hz, 1H), 7.58 (ddd, J = 8.5, 4.7, 2.3 Hz,1H), 7.46 (dd, J = 10.6, 8.5 Hz, 1H), 7.40-7.29 (m, 6H), 7.04 (q, J =1.8 Hz, 1H), 7.01-6.95 (m, 2H), 4.27 (s, 2H), 3.76 (s, 3H); (M + H)⁺ =633.6 +++ 14 243

¹H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.42 (s, 1H), 7.77-7.70 (m,2H), 7.56-7.50 (m, 2H), 7.41 (dd, J = 10.7, 9.1 Hz, 1H), 7.33-7.26 (m,6H), 7.23 (dd, J = 8.4, 0.8 Hz, 2H), 4.23 (s, 2H), 2.31 (s, 3H); (M +H)⁺ = 617.6 +++ 14 244

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.8 Hz, 1H), 7.66 (dt, J = 6.7,2.1 Hz, 1H), 7.59 (q, J = 1.6 Hz, 2H), 7.55 (dd, J = 10.9, 1.8 Hz, 1H),7.53- 7.46 (m, 2H), 7.45-7.36 (m, 6H), 7.33 (ddd, J = 6.7, 4.9, 2.8 Hz,1H), 7.21 (t, J = 7.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H),2.17 (tt, J = 8.6, 5.6 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.97 (dt, J =11.2, 3.2 Hz, 2H), 0.73-0.58 (m, 2H); (M + H)⁺ = 603.7 − 112 245

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.3 Hz, 1H), 7.67 (t, J = 7.9Hz, 1H), 7.58 (s, 2H), 7.54 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.44 (dd, J= 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.5 Hz, 1H), 7.23 (d, J = 0.7Hz, 4H), 7.23-7.17 (m, 1H), 7.05 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 4.16 (s, 2H), 2.31 (s, 3H), 2.19 (tt, J = 8.6, 5.6 Hz, 1H),1.29 (t, J = 7.1 Hz, 3H), 1.03-0.91 (m, 2H), 0.70-0.60 (m, 2H); (M + H)⁺= 635.7 + 112 246

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.4 Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.60-7.43 (m, 5H), 7.38 (dd, J = 10.7, 8.5 Hz, 1H), 7.34-7.27(m, 1H), 7.27-7.13 (m, 3H), 7.06 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 4.17 (s, 2H), 2.26- 2.09 (m, 1H), 1.35- 1.22 (m, 3H), 1.03-0.90 (m, 2H), 0.65 (td, J = 6.1, 4.4 Hz, 2H); (M + H)⁺ = 639.7 + 112 247

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.70 (t, J = 7.9 Hz, 1H),7.64-7.55 (m, 3H), 7.47 (dd, J = 7.6, 2.3 Hz, 1H), 7.44- 7.35 (m, 3H),7.28 (t, J = 8.9 Hz, 2H), 7.22 (d, J = 11.2 Hz, 1H), 7.08 (dd, J = 8.1,1.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 2.22 (tt, J = 8.5,5.7 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.08-0.92 (m, 2H), 0.73-0.64 (m,2H); (M + H)⁺ = 639.7 + 112 248

¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 0.5 Hz, 1H), 7.69 (t, J = 7.9Hz, 1H), 7.62-7.50 (m, 4H), 7.42-7.33 (m, 2H), 7.24-7.16 (m, 1H), 7.09(dd, J = 8.2, 1.6 Hz, 1H), 7.03-6.96 (m, 2H), 6.92 (dt, J = 7.7, 1.4 Hz,1H), 4.32 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 3.78 (s, 3H), 3.17 (dd, J =5.2, 0.5 Hz, 1H), 2.21 (tt, J = 8.5, 5.6 Hz, 1H), 1.36- 1.27 (m, 3H),1.06-0.95 (m, 2H), 0.67 (td, J = 6.2, 4.4 Hz, 2H); (M + H)⁺ = 651.7 −112 249

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.28 (s, 1H), 7.67 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.53 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.44(dd, J = 7.7, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.6 Hz, 1H), 7.23 (s,4H), 7.20 (dd, J = 11.3, 1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H),4.15 (s, 2H), 3.14 (d, J = 3.9 Hz, 1H), 2.31 (s, 3H), 2.23 (tt, J = 8.6,5.6 Hz, 1H), 1.01-0.89 (m, 2H), 0.68-0.59 (m, 2H); (M + H)⁺ = 607.7 +++112 250

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.29 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.61-7.54 (m, 3H), 7.52 (dd, J = 7.5, 2.3 Hz, 1H), 7.47(td, J = 8.0, 6.1 Hz, 1H), 7.37 (dd, J = 10.7, 8.5 Hz, 1H), 7.31 (dd, J= 10.2, 2.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.20 (s, 0H), 7.05 (dd, J = 8.0,1.5 Hz, 1H), 4.17 (s, 2H), 2.23 (tt, J = 8.5, 5.5 Hz, 1H), 1.03-0.90 (m,2H), 0.68-0.52 (m, 2H); (M + H)⁺ = 611.6 +++ 112 251

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.31 (s, 1H), 7.68 (t, J =7.9 Hz, 1H), 7.64-7.57 (m, 3H), 7.55 (dd, J = 7.6, 2.3 Hz, 1H), 7.50(td, J = 8.1, 6.2 Hz, 1H), 7.40 (dd, J = 10.7, 8.5 Hz, 1H), 7.34 (d, J =10.2 Hz, 1H), 7.29-7.23 (m, 1H), 7.23 (s, 0H), 7.08 (dd, J = 8.0, 1.6Hz, 1H), 4.20 (s, 2H), 2.38-2.17 (m, 1H), 1.08- 0.86 (m, 2H), 0.76-0.52(m, 2H); (M + H)⁺ = 611.6 +++ 112 252

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.30 (s, 1H), 7.69 (t, J =7.9 Hz, 1H), 7.58 (d, J = 4.8 Hz, 2H), 7.56- 7.52 (m, 1H), 7.41-7.34 (m,2H), 7.24-7.17 (m, 1H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 7.02-6.99 (m,1H), 6.98 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.92 (dd, J = 7.7, 1.3 Hz,1H), 4.19 (s, 2H), 3.78 (s, 3H), 2.34-2.13 (m, 1H), 1.10-0.93 (m, 2H),0.71-0.61 (m,2H); (M + H)⁺ = 623.7 +++ 112 253

¹H NMR (400 MHz, DMSO-d6) δ 7.59- 7.44 (m, 3H), 7.42 (s, 2H), 7.33 (dd,J = 10.7, 8.5 Hz, 1H), 7.24 (d, J = 1.6 Hz, 3H), 7.17 (t, J = 7.8 Hz,1H), 4.10 (s, 2H), 2.34-2.27 (m, 3H), 2.19 (s, 0H), 0.95 (d, J = 9.0 Hz,2H), 0.62 (d, J = 5.6 Hz, 2H); (M +H)⁺ = 607.7 +++ 112 254

(M + H)⁺ = 611.6 +++ 112 255

¹H NMR (400 MHz, DMSO-d6) δ 7.62- 7.44 (m, 4H), 7.44- 7.27 (m, 3H),7.28- 7.11 (m, 3H), 4.11 (s, 2H), 2.18 (s, 0H), 0.96 (d, J = 8.1 Hz,2H), 0.62 (d, J = 5.6 Hz, 2H); (M + H)⁺ = 611.6 +++ 112 256

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.30 (s, 1H), 7.60-7.46 (m,4H), 7.40 (s, 2H), 7.40- 7.29 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.05-6.83 (m, 3H), 4.11 (s, 2H), 3.75 (s, 3H), 2.18 (tt, J = 8.5, 5.6 Hz,1H), 1.03-0.89 (m, 2H), 0.68-0.55 (m, 2H); (M + H)⁺ = 623.7 +++ 112 257

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.72 (d, J =8.2 Hz, 2H), 7.64 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 7.57 (dd, J = 7.6,2.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.42-7.34 (m, 4H), 7.32 (d, J = 9.4 Hz,4H), 4.17 (s, 2H), 3.17 (d, J = 6.9 Hz, 2H), 1.14 (h, J = 5.9, 5.3 Hz,1H), 0.33 (dt, J = 8.3, 2.8 Hz, 2H), 0.28-0.15 (m, 2H); (M + H)⁺ = 589.7+++ 112 258

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.60- 7.49 (m, 4H), 7.35- 7.23 (m, 1H), 7.14(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 4.13 (s,2H), 3.15 (d, J = 6.8 Hz, 2H), 2.87 (p, J = 7.3 Hz, 1H), 2.05- 1.86 (m,2H), 1.69 (tdd, J = 9.3, 5.2, 2.7 Hz, 1H), 1.58 (dddd, J = 11.9, 10.4,6.0, 2.9 Hz, 3H), 1.11 (pd, J = 7.7, 3.7 Hz, 1H), 0.39-0.29 (m, 2H),0.21 (dd, J = 5.0, 1.6 Hz, 2H); (M + H)⁺ = 623.7 +++ 145 259

¹H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.73-7.53 (m, 3H), 7.49 (ddd,J = 8.5, 4.8, 2.3 Hz, 1H), 7.37-7.09 (m, 3H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 5.93-5.74 (m, 1H), 4.11 (s, 2H), 3.21-3.05 (m, 4H), 2.62 (t, J =5.7 Hz, 2H), 2.31 (d, J = 13.8 Hz, 5H), 1.11 (dd, J = 9.3, 3.9 Hz, 1H),0.31 (dt, J = 8.2, 2.8 Hz, 2H), 0.27-0.12 (m, 2H); (M + H)⁺ = 626.7 +++145 260

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.76 (dd, J = 7.3,2.2 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.57- 7.49 (m, 3H), 7.30 (dd, J =9.8, 8.6 Hz, 1H), 7.14- 7.07 (m, 1H), 7.06-6.99 (m, 1H), 4.37-4.24 (m,2H), 4.16 (s, 2H), 4.08 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.31 (td, J =7.1, 0.8 Hz, 3H), 1.18-1.05 (m, 1H), 0.33 (dt, J = 8.2, 2.8 Hz, 2H),0.27- 0.19 (m, 2H); (M + H)⁺ = 599 + 145 261

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.15 (s, 1H), 7.64 (td, J =7.9, 3.0 Hz, 2H), 7.61-7.53 (m, 5H), 7.50 (dd, J = 6.9, 2.2 Hz, 1H),7.44 (ddd, J = 8.6, 5.1, 2.3 Hz, 1H), 7.31 (td, J = 9.0, 3.6 Hz, 2H),7.16- 6.98 (m, 4H), 4.13 (s, 2H), 3.80 (s, 2H), 3.25-3.12 (m, 6H), 3.02(qd, J = 8.8, 3.4 Hz, 6H), 2.42 (d, J = 6.8 Hz, 2H), 2.11- 1.93 (m, 4H),1.75 (ddq, J = 13.6, 9.1, 4.3 Hz, 4H), 1.19- 1.04 (m, 1H), 1.00- 0.85(m, 1H), 0.43- 0.37 (m, 2H), 0.36- 0.30 (m, 2H), 0.24 0.18 (m,2H), 0.14-0.08 (m, 2H); (M + H)⁺ = 639 +++ 145 262

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.56-7.47 (m, 2H), 7.27 (t, J = 9.0 Hz, 1H),7.13 (dd, J = 11.2, 1.5 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H), 4.12(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.57 (tt, J = 8.3, 5.0 Hz, 1H), 1.11(ddd, J = 13.1, 9.1, 5.9 Hz, 1H), 0.95- 0.86 (m, 2H), 0.78- 0.70 (m,2H), 0.37- 0.27 (m, 2H), 0.25- 0.16 (m, 2H); (M + H)⁺ = 597 +++ 145 263

¹H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.16 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.55-7.46 (m, 1H), 7.36 (t, J = 9.0 Hz, 1H),7.12-6.99 (m, 2H), 3.81 (s, 2H), 3.63 (s, 8H), 2.41 (d, J = 6.8 Hz, 2H),0.99- 0.86 (m, 1H), 0.45- 0.35 (m, 2H), 0.16- 0.05 (m, 2H); (M + H)⁺ =654.7 +++ 145 264

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.28 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.54 (dd, J = 7.3, 1.9 Hz, 1H), 7.52-7.48 (m,1H), 7.27 (t, J = 9.0 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02(dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.15 (d, J = 6.8 Hz, 2H), 1.57(tt, J = 8.3, 5.0 Hz, 1H), 1.11 (ddd, J = 12.8, 7.9, 5.4 Hz, 1H),0.98-0.84 (m, 2H), 0.79- 0.67 (m, 2H), 0.32 (dt, J = 8.2, 2.8 Hz, 2H),0.23 0.14 (m, 2H); (M + H)⁺ = 595.6 +++ 145 265

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.59-7.52 (m, 4H), 7.30 (t, J = 9.4 Hz, 1H), 7.14 (dd, J =11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 5.53 (s, 1H), 4.14(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.45 (s, 6H), 1.20-1.05 (m, 1H),0.37-0.27 (m, 2H), 0.26-0.12 (m, 2H); (M + H)⁺ = 613.7 +++ 145 266

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.5 Hz, 1H), 7.71-7.52 (m, 6H),7.47 (td, J = 7.6, 2.2 Hz, 1H), 7.34 (dd, J = 8.2, 2.3 Hz, 2H),7.27-7.16 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 4.30 (qd, J = 7.1, 2.3 Hz,2H), 4.17 (s, 2H), 3.21-3.08 (m, 2H), 2.30 (d, J = 2.1 Hz, 3H), 1.30(td, J = 7.1, 2.3 Hz, 3H), 1.15 (ddd, J = 9.8, 5.2, 2.0 Hz, 1H), 0.32(td, J = 5.8, 5.4, 2.7 Hz, 2H), 0.24 (d, J = 4.9 Hz, 2H); (M + H)⁺ =631.8 + 145 267

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.59(s, 2H), 7.26 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 11.4, 1.6 Hz, 1H), 7.04(ddd, J = 14.9, 7.5, 1.5 Hz, 2H), 6.95 (dd, J = 8.3, 2.5 Hz, 1H), 6.81(t, J = 2.0 Hz, 1H), 4.10 (s, 2H), 3.72-3.60 (m, 4H), 3.15 (d, J = 6.9Hz, 2H), 2.95-2.83 (m, 4H), 1.12 (dtt, J = 14.8,7.2,3.7 Hz, 1H),0.37-0.27 (m, 2H), 0.24-0.17 (m, 2H); (M + H)⁺ = 598.7 +++ 145 268

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.64 (t, J = 7.9Hz, 1H), 7.59-7.49 (m, 4H), 7.31-7.23 (m, 1H), 7.14 (dd, J = 11.3, 1.6Hz, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H), 4.30 (qd, J = 7.1, 0.8 Hz, 2H),4.13 (s, 2H), 3.15 (d, J = 6.8 Hz, 2H), 2.87 (p, J = 7.2 Hz, 1H),2.05-1.90 (m, 2H), 1.79-1.66 (m, 1H), 1.64-1.50 (m, 4H), 1.31 (td, J =7.1, 0.7 Hz, 3H), 1.18- 1.02 (m, 2H), 0.33 (dt, J = 8.1, 2.8 Hz, 2H),0.28-0.17 (m, 2H); (M + H)⁺ = 651.8 − 145 269

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 7.53 (d, J = 6.7 Hz, 3H), 7.51-7.44 (m, 0H), 7.41-7.30 (m, 2H),7.12 (d, J = 11.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 4.30 (q, J = 7.1Hz, 2H), 4.13 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.02 (s, 3H), 1.41-1.22(m, 3H), 1.12 (s, 2H), 0.43-0.29 (m, 2H), 0.23 (q, J = 4.9 Hz, 2H); (M +H)⁺ = 579.7 + 145 270

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.59-7.50 (m, 3H), 7.50-7.44 (m, 1H), 7.39-7.30 (m, 2H),7.12 (dd, J = 11.5, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13(s, 2H), 3.19-3.07 (m, 3H), 2.02 (s, 3H), 1.19- 0.97 (m, 1H), 0.38- 0.27(m, 2H), 0.27- 0.10 (m, 2H); (M + H)⁺ = 551.6 +++ 145 271

(M + H)⁺ = 465 + 16 272

(M + H)⁺ = 509 − 112 273

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.74-7.64 (m, 2H), 7.45-7.35(m, 2H), 7.34-7.27 (m, 3H), 7.22 (s, 2H). 7.14-7.07 (m, 2H), 4.15 (q, J= 7.1 Hz, 2H), 2.55-2.49 (m, 1H), 1.94-1.39 (m, 7H), 1.26-1.11 (m, 6H);(M + H)⁺ = 553 − 33 274

¹H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78-7.68 (m, 4H), 7.42-7.26(m, 3H), 7.22 (s, 2H), 7.18-7.09 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.88(tt, J = 12.0, 3.1 Hz, 1H), 1.96-1.44 (m, 7H), 1.39-0.98 (m, 6H); (M +H)⁺ = 553 − 33 275

(M + H)⁺ = 531 + 112 276

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.75-7.64 (m,4H), 7.59 (dt, J = 7.7, 1.3 Hz, 1H), 7.52-7.46 (m, 1H), 7.45-7.37 (m,4H), 7.37-7.30 (m, 3H), 7.28 (s, 2H), 4.16 (s, 2H), 3.16 (m, 2H), 1.13(ddtd, J = 13.0, 8.0, 6.9, 4.9 Hz, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m,2H); (M + H)⁺ = 571 +++ 141 277

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.79-7.61 (m,2H), 7.37-7.09 (m, 6H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 3.84 (s,2H), 3.71 (s, 3H), 2.40 (d, J = 6.8 Hz, 2H), 0.99-0.82 (m, 1H),0.43-0.33 (m, 2H), 0.13-0.05 (m, 2H); (M + H)⁺ = 543 + 141 278

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.79-7.61 (m,2H), 7.37-7.09 (m, 6H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 3.84 (s,2H), 3.71 (s, 3H), 2.40 (d, J = 6.8 Hz, 2H), 0.99-0.82 (m, 1H),0.43-0.33 (m, 2H), 0.13-0.05 (m, 2H); (M + H)⁺ = 543 +++ 141 279

(M + H)⁺ = 599 + 141 280

(M + H)⁺ = 585 + 141 281

(M + H)⁺ = 585 +++ 141 282

(M + H)⁺ = 603 +++ 141 283

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.70-7.63 (m,2H), 7.52 (dd, J = 7.6, 2.2 Hz, 1H), 7.40-7.15 (m, 11H), 3.85 (s, 2H),2.39 (d, J = 6.8 Hz, 2H), 2.29 (s, 3H), 0.91 (dddd, J = 11.6, 8.1, 5.0,2.0 Hz, 1H), 0.42-0.33 (m, 2H), 0.13-0.04 (m, 2H); (M + H)⁺ = 603 + 141284

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.26 (s, 1H), 7.72-7.66 (m,2H), 7.61-7.48 (m, 2H), 7.35-7.19 (m, 10H), 4.13 (s, 2H), 3.14 (d, J =6.9 Hz, 2H), 2.31 (s, 3H), 1.17-1.05 (m, 1H), 0.33-0.26 (m, 2H),0.22-0.15 (m, 2H); (M + H)⁺ = 603 +++ 141 285

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.55-7.44 (m,3H), 7.39 (s, 2H), 7.39- 7.13 (m, 8H), 3.83 (s, 2H), 2.43 (d, J = 6.8Hz, 2H), 2.30 (s, 3H), 0.98-0.86 (m, 1H), 0.43-0.33 (m, 2H), 0.15-0.06(m, 2H); (M + H)⁺ = 621 + 145 286

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.18 (s, 1H), 7.68-7.57 (m,3H), 7.55 (s, 2H), 7.48- 7.38 (m, 3H), 7.30 (ddd, J = 7.6, 1.8, 1.1 Hz,1H), 7.22-7.15 (m, 2H), 7.09 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J =8.1, 1.6 Hz, 1H), 3.86 (s, 2H), 2.42 (d, J = 6.8 Hz, 2H), 2.28 (s, 3H),1.00-0.87 (m, 1H), 0.44-0.34 (m, 2H), 0.15-0.06 (m, 2H); (M + H)⁺ =603 + 145 287

¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.17 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.58-7.47 (m, 1H), 7.40-7.24 (m, 5H),7.24-7.17 (m, 2H), 7.22-7.06 (m, 2H), 7.09-6.97 (m, 1H), 3.86 (s, 2H),2.41 (d, J = 6.8 Hz, 2H), 2.30 (s, 3H), 0.92 (dddd, J = 11.6, 8.1, 5.0,1.9 Hz, 1H), 0.43-0.34 (m, 2H), 0.14-0.06 (m, 2H); (M + H)⁺ = 621 + 145288

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.24 (s, 1H), 7.69-7.53 (m,2H), 7.57 (s, 2H), 7.49 (dd, J = 7.6, 2.3 Hz, 1H), 7.32 (dd, J = 10.7,8.5 Hz, 1H), 7.24 (s, 3H), 7.26- 7.12 (m, 2H), 7.04 (dd, J = 8.1, 1.6Hz, 1H), 4.14 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.31 (s, 3H), 1.18-1.00(m, 1H), 0.36-0.25 (m, 2H), 0.23-0.15 (m, 2H); (M + H)⁺ = 621 +++ 145289

(M + H)⁺ = 589 + 145 290

(M + H)⁺ = 589 +++ 145 291

¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.18 (s, 1H), 7.71-7.57 (m,3H), 7.57-7.49 (m, 4H), 7.46 (td, J = 7.7, 0.6 Hz, 1H), 7.43-7.34 (m,2H), 7.37-7.26 (m, 2H), 7.13-6.99 (m, 2H), 3.87 (s, 2H), 2.43 (d, J =6.8 Hz, 2H), 1.02-0.86 (m, 1H), 0.44-0.34 (m, 2H), 0.15-0.07 (m, 2H);(M + H)+ = 589 + 145 292

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.16 (s, 1H), 7.70-7.63 (m,2H), 7.68-7.43 (m, 3H), 7.42-7.27 (m, 2H), 7.28-7.17 (m, 6H), 3.85 (s,2H), 2.39 (d, J = 6.8 Hz, 2H), 0.92 (dddd, J = 13.3, 8.1, 5.0, 2.0 Hz,1H), 0.42- 0.33 (m, 2H), 0.13- 0.04 (m, 2H); (M + H)+ = 607 + 145 293

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.16 (s, 1H), 7.72-7.63 (m,2H), 7.50 (dd, J = 7.6, 2.2 Hz, 1H), 7.40-7.26 (m, 4H), 7.29-7.20 (m,4H), 7.12-7.04 (m, 2H), 3.85 (s, 2H), 2.39 (d, J = 6.8 Hz, 2H), 1.90(tt, J = 8.3, 5.1 Hz, 1H), 0.98- 0.88 (m, 3H), 0.73- 0.62 (m, 2H), 0.42-0.31 (m, 2H), 0.15- 0.04 (m, 2H); (M + H)⁺ = 629 + 145 294

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.77- 7.64 (m,2H), 7.60 (ddd, J = 8.5, 4.7, 2.3 Hz, 1H), 7.52 (dd, J = 7.7, 2.3 Hz,1H), 7.41-7.28 (m, 4H), 7.31-7.18 (m, 2H), 7.18- 7.08 (m, 2H), 4.16 (s,2H), 3.21-3.14 (m, 2H), 1.94 (tt, J = 8.3,5.0 Hz, 1H), 1.21-1.07 (m,1H), 1.05-0.92 (m, 2H), 0.79- 0.65 (m, 2H), 0.38-0.30 (m, 2H), 0.25-0.18(m, 2H); (M + H)⁺ = 629 +++ 145 295

(M + H)⁺ = 592 + 141 296

(M + H)⁺ = 592 +++ 141 297

¹H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.76-7.70 (m, 2H), 7.69-7.62(m, 3H), 7.48 (td, J = 7.6, 0.7 Hz, 1H), 7.45-7.31 (m, 8H), 7.30 (s,2H), 4.40-4.35 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz,7H); (M + H)⁺ = 653 − 49 298

¹H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 7.68-7.58 (m, 4H), 7.49-7.43(m, 2H), 7.44-7.33 (m, 3H), 7.34-7.27 (m, 2H), 7.25-7.18 (m, 4H), 3.99(s, 2H), 1.37-1.24 (m, 2H), 1.04 (s, 2H); (M + H)⁺ = 653 + 49 299

¹H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.31 (s, 1H), 7.73-7.65 (m,2H), 7.70-7.57 (m, 3H), 7.49-7.40 (m, 1H), 7.43-7.24 (m, 10H), 4.33 (s,2H), 1.81- 0.93 (m, 4H); (M + H)⁺ = 625 + 49 300

¹H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.31 (s, 1H), 7.68-7.48 (m,4H), 7.50-7.36 (m, 8H), 7.39-7.28 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H),4.27 (s, 2H), 1.73-1.10 (m, 4H); (M + H)⁺ = 643 ++ 49 301

(M + H)⁺ = 643 + 49 302

¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.30 (s, 1H), 7.67-7.54 (m,6H), 7.50-7.40 (m, 1H), 7.44-7.34 (m, 4H), 7.39-7.27 (m, 1H), 7.19 (dd,J = 11.4, 1.6 Hz, 1H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.34 (s, 2H),1.81-0.93 (m, 4H); (M + H)⁺ = 643 + 49 303

¹H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.23 (s, 1H), 7.72-7.56 (m,4H), 7.54-7.28 (m, 7H), 7.32-7.16 (m, 4H), 3.93 (s, 2H), 3.70 (q, J =11.2 Hz, 2H); (M + H)⁺ = 599 + 49 304

¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.30 (s, 1H), 7.72-7.57 (m,5H), 7.47 (td, J = 7.7, 0.6 Hz, 1H), 7.45-7.23 (m, 9H), 4.66 (q, J =10.5 Hz, 2H), 4.26 (s, 2H); (M + H)⁺ = 599 ++ 49 305

¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.71-7.63 (m, 2H), 7.53 (dd,J = 7.6, 2.2 Hz, 1H), 7.40-7.26 (m, 4H), 7.29-7.21 (m, 6H), 3.85 (s,2H), 2.88 (hept, J = 6.9 Hz, 1H), 2.39 (d, J = 6.8 Hz, 2H), 1.19 (s,sH), 1.18 (s, 3H), 0.92 (dddd, J = 11.8, 6.8, 5.6, 2.9 Hz, 1H),0.44-0.31 (m, 2H), 0.15-0.04 (m, 2H); (M + H)⁺ = 631 + 145 306

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.73-7.66 (m,2H), 7.61-7.46 (m, 2H), 7.38-7.20 (m, 10H), 4.13 (s, 2H), 3.14 (d, J =6.9 Hz, 2H), 2.89 (hept, J = 6.9 Hz, 1H), 1.21 (s, 3H), 1.19 (s, 3H),1.15- 1.04 (m, 1H), 0.35- 0.26 (m, 2H), 0.23- 0.14 (m, 2H); (M + H)⁺ =631 +++ 145 307

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.59-7.44 (m,4H), 7.42 (s, 2H), 7.32 (dd, J = 10.8, 8.5 Hz, 1H), 7.24 (s, 1H), 7.24(s, 3H), 7.14 (t, J = 7.8 Hz, 1H), 4.09 (s, 2H), 3.15 (d, J = 6.9 Hz,2H), 2.50 (s, 1H), 2.31 (s, 3H), 1.15-1.02 (m, 1H), 0.35-0.14 (m, 4H);(M + H)⁺ = 621 +++ 145 308

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.17 (s, 1H), 7.60-7.41 (m,5H), 7.44-7.14 (m, 7H), 3.84 (s, 2H), 2.52- 2.51 (m, 2H), 0.99- 0.84 (m,1H), 0.43- 0.34 (m, 2H), 0.15- 0.06 (m, 2H); (M + H)⁺ = 625 + 145 309

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.62-7.49 (m,2H), 7.49 (ddd, J = 8.4, 6.3, 2.1 Hz, 2H), 7.42 (s, 2H), 7.39 (ddd, J =8.9, 5.4, 1.4 Hz, 2H), 7.34 (dd, J = 10.7, 8.6 Hz, 1H), 7.31-7.21 (m,2H), 7.14 (t, J = 7.8 Hz, 1H), 4.09 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),1.15-1.02 (m, 1H), 0.35-0.26 (m, 2H), 0.29-0.15 (m, 2H); (M + H)⁺ = 625+++ 145 310

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.26 (s, 1H), 7.73-7.65 (m,2H), 7.62 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 7.49 (dd, J = 7.6, 2.3 Hz,1H), 7.41-7.29 (m, 3H), 7.32-7.19 (m, 6H), 4.13 (s, 2H), 3.15 (d, J =6.9 Hz, 2H), 2.50 (s, 1H), 1.19-1.02 (m, 1H), 0.35-0.24 (m, 2H),0.27-0.15 (m, 2H); (M + H)⁺ = 607 +++ 145 311

(M + H)⁺ = 599 +++ 14, 18 312

(M + H)⁺ = 603 +++ 14, 18 313

(M + H)⁺ = 603 +++ 14, 18 314

(M + H)⁺ = 615 +++ 14, 18 315

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.66 (dd, J = 7.6, 2.2 Hz,1H), 7.52-7.36 (m, 5H), 7.40-7.27 (m, 4H), 7.26-7.16 (m, 2H), 4.10 (q, J= 7.1 Hz, 2H), 3.85 (s, 2H), 2.44 (d, J = 6.8 Hz, 2H), 1.10 (t, J = 7.1Hz, 3H), 0.99-0.86 (m, 1H), 0.44-0.34 (m, 2H), 0.16-0.07 (m, 2H); (M +H)⁺ = 653 − 141 316

(M + H)⁺ = 653 + 141 317

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.69 (dd, J = 7.6, 2.2 Hz,1H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (s, 2H), 7.52- 7.34 (m, 2H),7.38-7.31 (m, 1H), 7.35-7.27 (m, 2H), 7.21 (dddd, J = 9.0, 8.3, 2.6, 1.0Hz, 1H), 7.11 (dd, J= 11.4, 1.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H),4.10 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 2.41 (d, J = 6.8 Hz, 2H), 1.10(t, J = 7.1 Hz, 3H), 0.99- 0.87 (m, 1H), 0.44-0.34 − 141 (m, 2H),0.15-0.06 (m, 2H); (M + H)⁺ = 653 318

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.68-7.55 (m, 3H), 7.56 (s,2H), 7.48 (ddd, J = 8.4, 7.7, 6.2 Hz, 1H), 7.42-7.29 (m, 2H), 7.34-7.16(m, 2H), 7.21- 7.11 (m, 2H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.29 (q, J= 7.1 Hz, 2H), 4.17 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.30 (t, J = 7.1Hz, 3H), 1.25-0.96 (m, 1H), 0.37-0.19 (m, 4H); (M + H)⁺ = 653 − 141 319

(M + H)⁺ = 665 − 141 320

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.61-7.44 (m, 4H), 7.43-7.29(m, 4H), 7.14 (t, J = 7.8 Hz, 1H), 7.02-6.94 (m, 1H), 6.99-6.87 (m, 1H),4.29 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.76 (s, 3H), 3.15 (d, J = 6.9Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.20-0.95 (m, 0H), 0.36-0.17 (m, 4H);(M + H)⁺ = 665 − 141 321

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.67-7.58 (m, 2H), 7.55 (s,2H), 7.44-7.27 (m, 3H), 7.15-6.89 (m, 6H), 4.10 (q, J = 7.1 Hz, 2H),3.88 (s, 2H), 3.72 (s, 3H), 2.41 (d, J = 6.8 Hz, 2H), 1.11 (t, J = 7.1Hz, 3H), 1.01-0.78 (m, 1H), 0.43-0.34 (m, 2H), 0.15-0.06 (m, 2H); (M +H)⁺ = 665 − 141 322

(M + H)⁺ = 665 + 141 323

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.18 (s, 1H), 7.66 (dd, J =7.6, 2.2 Hz, 1H), 7.52-7.25 (m, 7H), 7.39 (s, 2H), 7.26-7.15 (m, 2H),3.85 (s, 2H), 2.44 (d, J = 6.8 Hz, 2H), 1.00- 0.85 (m, 1H), 0.44- 0.34(m, 2H), 0.15- 0.07 (m, 2H); (M + H)⁺ = 625 + 141 324

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.64-7.55 (m,2H), 7.55-7.43 (m, 3H), 7.43-7.09 (m, 7H), 4.11 (s, 2H), 3.16 (d, J =6.9 Hz, 2H), 1.21- 0.95 (m, 1H), 0.36- 0.25 (m, 2H), 0.28- 0.15 (m, 2H);(M + H)⁺ = 625 +++ 141 325

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.17 (s, 1H), 7.73-7.58 (m,2H), 7.55 (s, 2H), 7.50- 7.40 (m, 1H), 7.44- 7.33 (m, 2H), 7.37- 7.29(m, 2H), 7.21 (dddd, J = 9.1, 8.3, 2.6, 1.0 Hz, 1H), 7.14-6.99 (m, 2H),3.88 (s, 2H), 2.41 (d, J = 6.8 Hz, 2H), 1.00-0.85 (m, 1H), 0.44-0.34 (m,2H), 0.15-0.06 (m, 2H); (M + H)⁺ = 625 + 141 326

(M + H)⁺ = 625 +++ 141 327

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.18 (s, 1H), 7.57 (dd, J =7.6, 2.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.42-7.23 (m, 5H), 7.20 (t, J = 7.9Hz, 1H), 7.06-6.97 (m, 2H), 6.92 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.85(s, 2H), 3.72 (s, 3H), 2.43 (d, J = 6.8 Hz, 2H), 1.06-0.78 (m, 1H),0.43-0.32 (m, 2H), 0.17-0.04 (m, 2H); (M + H)⁺ = 637 + 141 328

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.61-7.44 (m,4H), 7.41 (s, 2H), 7.39- 7.29 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H), 7.02-6.87 (m, 3H), 4.11 (s, 2H), 3.76 (s, 3H), 3.15 (d, J = 6.9 Hz, 2H),1.20-0.98 (m, 1H), 0.35-0.26 (m, 2H), 0.29-0.15 (m, 2H); (M + H)⁺ = 637+++ 141 329

¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.17 (s, 1H), 7.67-7.57 (m,2H), 7.55 (s, 2H), 7.43- 7.26 (m, 3H), 7.15- 6.97 (m, 4H), 6.92 (ddd, J= 8.3, 2.6, 0.9 Hz, 1H), 3.88 (s, 2H), 3.72 (s, 3H), 2.40 (d, J = 6.8Hz, 2H), 0.92 (dddd, J = 14.8, 8.0, 5.0, 1.9 Hz, 1H), 0.43- 0.34 (m,2H), 0.14- 0.06 (m, 2H); (M + H)⁺ = 637 + 141 330

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.68-7.54 (m,3H), 7.56 (s, 2H), 7.39- 7.29 (m, 2H), 7.15 (dd, J = 11.3, 1.6 Hz, 1H),7.09-6.86 (m, 4H), 4.16 (s, 2H), 3.75 (s, 3H), 3.14 (d, J = 6.9 Hz, 2H),1.11 (s, 1H), 0.36-0.27 (m, 2H), 0.24-0.15 (m, 2H); (M + H)⁺ = 637 +++141 331

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.71-7.62 (m,2H), 7.66-7.53 (m, 2H), 7.58 (s, 2H), 7.56- 7.29 (m, 6H), 7.19 (dd, J =11.4, 1.6 Hz, 1H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 4.17 (s, 2H), 3.16(d, J = 6.9 Hz, 2H), 1.23- 1.07 (m, 1H), 0.37- 0.28 (m, 2H), 0.31- 0.17(m, 2H); (M + H)⁺ = 589 +++ 141 332

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.71-7.53 (m,4H), 7.58 (s, 2H), 7.57- 7.40 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.26-7.15 (m, 3H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J =6.9 Hz, 2H), 2.30 (s, 3H), 1.23-1.01 (m, 1H), 0.37-0.28 (m, 2H),0.25-0.16 (m, 2H); (M + H)⁺ = 603 +++ 141 333

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.56(s, 2H), 7.32- 7.23 (m, 1H), 7.14 (dd, J = 11.3, 1.5 Hz, 1H), 7.12-7.01(m, 2H), 6.94- 6.83 (m, 2H), 4.58 (dq, J = 6.0, 3.0 Hz, 1H), 4.29 (q, J= 7.1 Hz, 2H), 4.11 (s, 2H), 3.12 (d, J = 6.9 Hz, 2H), 1.80-1.68 (m,2H), 1.68-1.59 (m, 3H), 1.59-1.47 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H),1.16-1.04 (m, 1H), 0.36-0.27 (m, 2H), 0.27-0.17 (m, 2H); (M + H)⁺ =625 + 120 334

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.73-7.65 (m, 2H), 7.32-7.22(m, 5H), 7.09 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.95-6.83 (m, 2H), 4.54(dq, J = 6.1, 3.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 3.11(d, J = 6.9 Hz, 2H), 1.78-1.41 (m, 8H), 1.30 (t, J = 7.1 Hz, 3H),1.14-1.10 m, 1H), 0.35-0.25 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ = 607 −141 335

¹H NMR (400 MHz, DMSO-d6) δ 8.49- 8.24 (m, 1H), 7.60- 7.45 (m, 2H), 7.41(s, 2H), 7.27 (ddd, J = 8.2, 7.7, 0.5 Hz, 1H), 7.18-7.02 (m, 2H),6.96-6.83 (m, 2H), 4.57 (dq, J = 5.9, 3.0 Hz, 1H), 4.29 (q, J = 7.1 Hz,2H), 4.06 (s, 2H), 3.13 (d, J = 7.0 Hz, 2H), 1.92-1.40 (m, 8H), 1.30 (t,J = 7.1 Hz, 3H), 1.23- 0.93 (m, 1H), 0.39- 0.26 (m, 2H), 0.24- 0.13 (m,2H); (M + H)⁺ = 625 + 120 336

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 0H), 8.27 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.18-7.07 (m, 2H),7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.94- 6.83 (m, 2H), 4.58 (tt, J = 5.7,2.5 Hz, 1H), 4.11 (s, 2H), 3.12 (d, J = 6.9 Hz, 2H), 1.78-1.46 (m, 8H),1.23-0.93 (m, 1H), 0.35-0.14 (m, 4H); (M + H)⁺ = 597 +++ 120 337

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.27 (s, 1H), 7.72-7.65 (m,2H), 7.32-7.19 (m, 6H), 7.09 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.95-6.82(m, 3H), 4.54 (dq, J = 6.1, 3.1 Hz, 1H), 4.09 (s, 2H), 3.11 (d, J = 6.9Hz, 2H), 1.78-1.69 (m, 2H), 1.69-1.57 (m, 4H), 1.57-1.46 (m, 4H),1.21-0.93 (m, 1H), 0.34-0.25 (m, 2H), 0.22-0.13 (m, 2H); (M + H)⁺ = 579+++ 120 338

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.58-7.45 (m, 2H), 7.41 (s,2H), 7.27 (t, J = 7.9 Hz, 1H), 7.16-7.02 (m, 2H), 6.93-6.83 (m, 2H),4.56 (tt, J = 5.6, 2.5 Hz, 1H), 4.05 (s, 2H), 3.13 (d, J = 6.9 Hz, 2H),1.80-1.46 (m, 8H), 1.20-0.82 (m, 1H), 0.34-0.26 (m, 2H), 0.26-0.14 (m,2H); (M + H)⁺ = 597 +++ 120 339

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.72-7.64 (m,2H), 7.42-7.20 (m, 10H), 7.16-7.07 (m, 2H), 7.00 (ddd, J = 8.3, 2.6, 1.0Hz, 1H), 5.01 (s, 2H), 4.09 (s, 2H), 3.11 (d, J = 6.9 Hz, 2H), 1.09(ddtd, J = 13.0, 7.9, 6.9, 5.0 Hz, 1H), 0.35-0.25 (m, 2H), 0.22-0.13 (m,2H); (M + H)⁺ = 601 +++ 120 340

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.42-7.24 (m, 6H), 7.16-7.05 (m, 3H), 7.00(ddt, J = 8.3, 2.6, 1.2 Hz, 2H), 5.03 (s, 2H), 4.10 (s, 2H), 3.12 (d, J= 6.9 Hz, 2H), 1.14-0.98 (m, 1H), 0.35-0.24 (m, 2H), 0.25-0.14 (m, 2H);(M + H)⁺ = 619 +++ 120 341

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.58-7.43 (m,2H), 7.43-7.24 (m, 8H), 7.16-6.96 (m, 4H), 5.04 (s, 2H), 4.05 (s, 2H),3.12 (d, J = 6.9 Hz, 2H), 1.18-0.96 (m, 1H), 0.34-0.25 (m, 2H),0.22-0.13 (m, 2H); (M + H)⁺ = 619 +++ 120 342

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.18 (s, 1H), 7.73- 7.63 (m,2H), 7.50-7.05 (m, 12H), 7.03 (ddd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.90 (dt,J = 7.6, 1.1 Hz, 1H), 5.05 (s, 2H), 3.79 (s, 2H), 2.36 (d, J = 6.8 Hz,2H), 0.98- 0.83 (m, 1H), 0.43- 0.31 (m, 2H), 0.12- 0.03 (m, 2H); (M +H)⁺ = 601 + 120 343

¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.69-7.54 (m, 2H), 7.58 (s,2H), 7.50 (dd, J = 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.6 Hz, 1H),7.24 (s, 3H), 7.29-7.13 (m, 2H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.29(q, J = 7.1 Hz, 2H), 4.15 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.32 (s,3H), 1.30 (t, J = 7.1 Hz, 3H), 1.21-1.00 (m, 1H), 0.37-0.26 (m, 2H),0.23 (dt, J = 5.1, 2.6 Hz, 2H); (M + H)⁺ = 649 + 141 344

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.67-7.41 (m, 9H), 7.38-7.29(m, 2H), 7.26-7.13 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.15(dd, J = 9.8, 6.1 Hz, 3H), 2.30 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H),1.25-0.96 (m, 0H), 0.37-0.19 (m, 4H); (M + H)⁺ = 631 − 145 345

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.63-7.45 (m, 4H), 7.43 (s,2H), 7.45-7.30 (m, 3H), 7.32-7.21 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H),4.29 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.30(t, J = 7.1 Hz, 3H), 1.20-0.91 (m, 0H), 0.37-0.18 (m, 4H); (M + H)⁺ =653 + 145 346

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.15 (s, 1H), 7.70-7.54 (m,5H), 7.50-7.40 (m, 3H), 7.30 (dt, J = 7.7, 1.3 Hz, 1H), 7.24-7.08 (m,3H), 7.13-7.02 (m, 1H), 3.92 (s, 2H), 2.29 (s, 3H), 1.77 (tt, J = 7.5,5.6 Hz, 1H), 0.85 (ddd, J = 6.9, 3.5, 1.6 Hz, 4H); (M + H)⁺ = 589 + 112347

¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.31 (s, 1H), 7.73-7.41 (m,7H), 7.31 (d, J = 8.2 Hz, 2H), 7.26-7.17 (m, 3H), 7.08 (dd, J = 8.2, 1.6Hz, 1H), 4.16 (s, 2H), 2.30 (s, 3H), 2.30-2.19 (m, 1H), 1.02-0.92 (m,2H), 0.70-0.61 (m, 2H); (M + H)⁺ = 589 +++ 112 348

(M + H)⁺ = 593 + 112 349

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.74-7.60 (m,2H), 7.60 (s, 2H), 7.59- 7.39 (m, 5H), 7.27- 7.18 (m, 3H), 7.08 (dd, J =8.1, 1.6 Hz, 1H), 4.17 (s, 2H), 2.25 (tt, J = 8.5, 5.5 Hz, 1H),1.04-0.93 (m, 2H), 0.73-0.62 (m, 2H); (M + H)⁺ = 593 +++ 112 350

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.15 (s, 1H), 7.78-7.69 (m,2H), 7.64 (t, J = 7.9 Hz, 1H), 7.55 (s, 2H), 7.52-7.39 (m, 4H),7.43-7.32 (m, 1H), 7.20-7.02 (m, 3H), 3.93 (s, 2H), 1.76 (tt, J = 7.6,5.5 Hz, 1H), 0.90-0.78 (m, 4H); (M + H)⁺ = 593 + 112 351

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.74-7.61 (m,3H), 7.59-7.44 (m, 4H), 7.49-7.35 (m, 2H), 7.26-7.04 (m, 4H), 4.18 (s,2H), 2.24 (tt, J = 8.5, 5.6 Hz, 1H), 1.04-0.91 (m, 2H), 0.72-0.61 (m,2H); (M + H)⁺ = 593 +++ 112 352

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.15 (s, 1H), 7.73-7.60 (m,3H), 7.55 (s, 2H), 7.48 (td, J = 7.7, 0.5 Hz, 1H), 7.37-7.25 (m, 2H),7.17-7.03 (m, 4H), 6.88 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.93 (s, 2H),3.29 (s, 9H), 1.75 (tt, J = 7.5, 5.6 Hz, 1H), 0.90-0.78 (m, 4H); (M +H)⁺ = 605 + 112 353

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.30 (s, 1H), 7.72-7.59 (m,3H), 7.59-7.40 (m, 4H), 7.36-7.25 (m, 1H), 7.20 (dd, J = 11.3, 1.6 Hz,1H), 7.12-7.03 (m, 2H), 6.93 (dddd, J = 21.2, 8.3, 2.2, 0.9 Hz, 2H),4.17 (s, 2H), 3.76 (s, 3H), 2.24 (tt, J = 8.5, 5.6 Hz, 1H), 1.01-0.90(m, 2H), 0.71-0.58 (m, 2H); (M + H)⁺ = 605 +++ 112 354

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.16 (s, 1H), 7.69-7.49 (m,3H), 7.54-7.46 (m, 1H), 7.50-7.39 (m, 5H), 7.33-7.15 (m, 4H), 3.90 (s,2H), 2.29 (s, 3H), 1.76 (p, J = 6.8 Hz, 1H), 0.87-0.80 (m, 4H); (M + H)⁺= 589 + 112 355

1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.31 (s, 1H), 7.69-7.49 (m,4H), 7.52-7.42 (m, 2H), 7.43 (s, 2H), 7.37- 7.28 (m, 2H), 7.25- 7.16 (m,3H), 4.11 (s, 2H), 2.30 (s, 3H), 2.21 (tt, J = 8.5, 5.6 Hz, 1H),1.02-0.92 (m, 2H), 0.69-0.60 (m, 2H); (M + H)+ = 589 +++ 112 356

(M + H)⁺ = 593 + 112 357

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.30 (s, 1H), 7.65 (dt, J =6.6, 2.1 Hz, 1H), 7.65-7.53 (m, 2H), 7.58-7.46 (m, 3H), 7.50-7.41 (m,4H), 7.29-7.16 (m, 3H), 4.11 (s, 2H), 2.21 (tt, J = 8.6, 5.6 Hz, 1H),1.02-0.91 (m, 2H), 0.71-0.60 (m, 2H); (M + H)⁺ = 593 +++ 112 358

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.15 (s, 1H), 7.72 (ddd, J =9.7, 1.8, 0.9 Hz, 2H), 7.55- 7.46 (m, 1H), 7.50 (s, 1H), 7.51-7.38 (m,4H), 7.40 (s, 2H), 7.36-7.10 (m, 3H), 3.91 (s, 2H), 1.82- 1.70 (m, 1H),0.89- 0.78 (m, 4H); (M + H)⁺ = 593 + 112 359

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.30 (s, 1H), 7.65 (dt, J =6.6, 2.1 Hz, 1H), 7.65-7.53 (m, 2H), 7.58-7.46 (m, 3H), 7.50-7.41 (m,4H), 7.29-7.16 (m, 3H), 4.11 (s, 2H), 3.14 (d, J = 2.7 Hz, 1H), 2.21(tt, J = 8.6, 5.6 Hz, 1H), 1.02- 0.91 (m, 2H), 0.71- 0.60 (m, 2H); (M +H)⁺ = 593 +++ 112 360

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.16 (s, 1H), 7.72- 7.61 (m,2H), 7.55-7.43 (m, 3H), 7.39 (s, 2H), 7.34-7.21 (m, 3H), 7.10 (dd, J =6.9, 1.3 Hz, 2H), 6.92-6.84 (m, 1H), 3.90 (s, 2H), 3.74 (s, 3H), 1.81-1.69 (m, 1H), 0.89- 0.79 (m, 4H); (M + H)⁺ = 605 + 112 361

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.72-7.60 (m,2H), 7.64 -7.48 (m, 2H), 7.53-7.43 (m, 2H), 7.41 (s, 2H), 7.36- 7.27 (m,1H), 7.20 (t, J = 7.8 Hz, 1H), 7.07 (dd, J = 2.5, 1.7 Hz, 1H), 6.93(dddd, J = 24.5, 8.3, 2.1, 0.9 Hz, 2H), 4.12 (s, 2H), 3.76 (s, 3H), 2.20(tt, J = 8.5, 5.6 Hz, 1H), 1.01-0.90 (m, 2H), 0.70-0.57 (m, 2H); (M +H)⁺ = 605 +++ 112 362

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.69-7.54 (m,2H), 7.58 (s, 2H), 7.50 (dd, J = 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7,8.6 Hz, 1H), 7.24 (s, 3H), 7.29- 7.13 (m, 2H), 7.04 (dd, J = 8.2, 1.6Hz, 1H), 4.15 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.32 (s, 3H), 1.20-0.96(m, 1H), 0.37-0.27 (m, 2H), 0.28-0.16 (m, 2H); (M + H)⁺ = 621 +++ 145363

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.67-7.59 (m,2H), 7.61-7.42 (m, 4H), 7.43 (s, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.26-7.12 (m, 3H), 4.11 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.30 (s, 3H),1.18-1.01 (m, 1H), 0.36-0.27 (m, 2H), 0.24-0.17(m, 2H); (M + H)⁺ = 603+++ 145 364

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.28 (s, 1H), 7.63-7.45 (m,4H), 7.43 (s, 2H), 7.44- 7.21 (m, 5H), 7.14 (t, J = 7.8 Hz, 1H), 4.10(s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.15- 1.02 (m, 0H), 0.36- 0.15 (m,4H); (M + H)⁺ = 625 +++ 145 365

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.74-7.62 (m,3H), 7.66-7.56 (m, 1H), 7.55 (s, 2H), 7.54- 7.43 (m, 1H), 7.47- 7.38 (m,2H), 7.29- 7.16 (m, 2H), 7.21- 7.12 (m, 1H), 7.07 (dd, J = 8.1, 1.6 Hz,1H), 4.18 (s, 2H), 3.15 (dd, J = 9.4, 5.6 Hz, 2H), 1.23-1.06 (m, 1H),0.37-0.17 (m, 4H); (M + H)⁺ = 607 +++ 145 366

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.70-7.58 (m,2H), 7.55 (s, 2H), 7.56- 7.41 (m, 2H), 7.41- 7.23 (m, 4H), 7.17- 6.99(m, 2H), 4.15 (s, 2H), 3.15 (dd, J = 5.8, 4.1 Hz, 2H), 1.21- 1.00 (m,1H), 0.37- 0.25 (m, 2H), 0.27- 0.16 (m, 2H); (M + H)⁺ = 625 +++ 145 367

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.69-7.30 (m,11H), 7.17 (dd, J = 11.3, 1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H),4.16 (s, 2H), 3.19-3.11 (m, 2H), 1.19-1.05 (m, 1H), 0.37-0.26 (m, 2H),0.26-0.16 (m, 2H); (M + H)⁺ = 607 +++ 145 368

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (s, 1H), 7.65-7.17 (m,11H), 7.27 (s, 2H), 4.14 (s, 2H), 3.19-3.11 (m, 3H), 1.18-0.96 (m, 1H),0.37-0.27 (m, 2H), 0.23-0.14 (m, 2H); (M + H)⁺ = 607 + 145 369

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.80 (s, 2H), 8.27 (s, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.60-7.47 (m, 3H), 7.39-7.21 (m, 2H), 7.12(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 5.93-5.87(m, 1H), 4.14-4.01 (m, 3H), 3.75- 3.68 (m, 2H), 3.25 (t, J = 6.0 Hz,2H), 3.15 (dd, J = 7.2, 5.8 Hz, 4H), 1.12 (dddd, J = 15.0, 10.0, 5.0,2.1 Hz, 1H), 0.37-0.28 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ = 612 +++145 370

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.76-7.66 (m,4H), 7.65-7.57 (m, 1H), 7.55-7.38 (m, 3H), 7.36-7.13 (m, 6H), 4.18 (s,2H), 3.17 (d, J = 6.9 Hz, 2H), 1.23- 0.98 (m, 1H), 0.38- 0.17 (m, 4H);(M + H)⁺ = 589 +++ 141 371

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.64(ddq, J = 7.3, 3.5, 2.3, 1.8 Hz, 2H), 7.59-7.46 (m, 1H), 7.43-7.29 (m,2H), 7.30-7.12 (m, 3H), 7.12-7.02 (m, 1H), 4.20 (s, 2H), 3.20-3.09 (m,2H), 1.23-0.93 (m, 0H), 0.38-0.25 (m, 2H), 0.29-0.16 (m, 2H); (M + H)⁺ =624 +++ 141 372

¹H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.74-7.65 (m, 2H), 7.36 (dt, J= 7.6, 1.5 Hz, 1H), 7.33- 7.18 (m, 7H), 4.09 (s, 2H), 3.14 (d, J = 6.9Hz, 2H), 2.89 (tt, J = 9.8, 7.5 Hz, 1H), 1.96- 1.84 (m, 1H), 1.71- 1.48(m, 3H), 1.42- 1.25 (m, 1H), 1.16- 1.03 (m, 1H), 0.36- 0.15 (m, 4H);(M + H)⁺ = 563 +++ 146 373

(M + H)⁺ = 599 +++ 146 374

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.44 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.27-7.16 (m, 2H), 7.20-7.11 (m, 2H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 4.10(s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.78-2.66 (m, 1H), 1.72 (dd, J = 9.7,6.4 Hz, 2H), 1.61 (d, J = 11.8 Hz, 3H), 1.37-1.23 (m, 2H), 1.15 (s, 2H),1.20-1.03 (m, 2H), 0.38-0.29 (m, 2H), 0.26- 0.17 (m, 2H); (M + H)⁺ = 613+++ 146 375

¹H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.56(s, 2H), 7.52- 7.38 (m, 2H), 7.23-7.09 (m, 2H), 7.04 (dd, J = 8.1, 1.6Hz, 1H), 4.09 (s, 2H), 3.16-3.09 (m, 3H), 2.07 (d, J = 3.8 Hz, 2H),1.90-1.79 (m, 2H), 1.85 (s, 4H), 1.69-1.64 (m, 3H), 1.52 (d, J = 12.9Hz, 3H), 1.42 (d, J = 12.6 Hz, 2H), 1.18- 1.02 (m, 1H), 0.35-0.24 (m,2H), 0.25-0.14 (m, 2H); (M + H)⁺ = 665 ++ 146 376

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.31 (s, 1H), 7.96-7.81 (m,3H), 7.64 (td, J = 7.9, 5.8 Hz, 2H), 7.56 (s, 2H), 7.13 (dd, J = 11.4,1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.17 (s, 2H), 3.18 (d, J =6.9 Hz, 2H), 1.31- 1.00 (m, 1H), 0.39- 0.25 (m, 2H), 0.29- 0.18 (m, 2H);(M + H)⁺ = 639 +++ 141 377

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.69-7.56 (m, 3H), 7.58 (s,2H), 7.49 (ddd, J = 8.4, 7.7, 6.2 Hz, 1H), 7.43- 7.29 (m, 2H), 7.30-7.13 (m, 3H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H),3.31 (s, 1H), 3.16 (d, J = 6.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.15(td, J = 7.4, 5.6 Hz, 1H), 0.38- 0.20 (m, 4H); (M + H)⁺ = 653 − 141 378

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.67-7.54(m,1H), 7.55 (s, 2H), 7.46- 7.36 (m, 2H), 7.22- 7.06 (m, 2H), 7.02 (dd, J =8.1, 1.6 Hz, 1H), 5.81-5.66 (m, 1H), 5.00-4.87 (m, 2H), 4.13 (s, 2H),3.15 (d, J = 6.9 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.27- 2.17 (m, 2H),1.24-1.05 (m, 1H), 0.38-0.26 (m, 2H), 0.29-0.16 (m, 2H); (M + H)⁺ = 585+++ 146 379

(M + H)⁺ = 613 +++ 145 380

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.60- 7.47 (m, 3H), 7.32 (s, 1H), 7.29-7.13 (m, 2H), 7.04(dd, J = 8.1, 1.6 Hz, 1H), 5.91 (d, J = 16.9 Hz, 1H), 4.33 (s, 1H), 4.13(s, 2H), 4.06 (s, 1H), 3.79 (s, 1H), 3.61 (s, 1H), 3.16 (d, J = 6.9 Hz,2H), 2.25 (s, 1H), 2.02 (s, 1H), 2.11-1.75 (m, 1H), 1.22-1.05 (m, 1H),0.74 (s, 3H), 0.72 (s, 1H), 0.38-0.28 (m, 2H), 0.26-0.17 (m, 2H); (M +H)⁺ = 680 +++ 145 381

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.54 (s, 2H), 7.48-7.30 (m, 2H), 7.21-7.05 (m, 2H), 7.01(dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),2.60-2.49 (m, 1H), 2.32 (dd, J = 13.2, 7.9 Hz, 1H), 1.48 (dp, J = 13.5,6.9 Hz, 1H), 1.37-1.18 (m, 1H), 1.17-1.00 (m, 1H), 0.89-0.77 (m, 3H),0.70 (d, J = 6.6 Hz, 3H), 0.37- 0.28 (m, 2H), 0.25- 0.16 (m, 2H); (M +H)⁺ = 601 +++ 146 382

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.54 (s, 2H), 7.48-7.30 (m, 2H), 7.21-7.05 (m, 2H), 7.01(dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.60-2.49 (m, 1H), 2.32 (dd, J = 13.2, 7.9 Hz, 1H), 1.48 (dp, J = 13.5, 6.9Hz, 1H), 1.37-1.18 (m, 1H), 1.17-1.00 (m, 1H), 0.89-0.77 (m, 3H), 0.70(d, J = 6.6 Hz, 3H), 0.37- 0.28 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ =585 +++ 146 383

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.68-7.58 (m,1H), 7.56 (s, 2H), 7.46- 7.30 (m, 2H), 7.20- 7.06 (m, 2H), 7.03 (ddd, J= 8.4, 6.8, 1.6 Hz, 1H), 4.12 (d, J = 5.3 Hz, 2H), 3.19- 3.02 (m,3H),1.09- 1.02 (d, J = 6.9 Hz, 6H), 0.81 (t, J = 7.3 Hz, 1H), 0.38-0.28 (m,2H), 0.25-0.17 (m, 2H); (M + H)⁺ = 573 +++ 146 384

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.50-7.35 (m, 2H), 7.28-7.19 (m, 2H),7.21-7.11 (m, 2H), 7.16-7.01 (m, 3H), 6.98 (dd, J = 8.1, 1.6 Hz, 1H),4.35 (q, J = 7.2 Hz, 1H), 4.08 (s, 2H), 3.13 (dd, J = 7.0, 4.0 Hz, 2H),1.41 (d, J = 7.2 Hz, 3H), 1.20-0.96 (m, 1H), 0.31 (dt, J = 9.1, 2.9 Hz,2H), 0.24-0.15 (m, 2H); (M + H)⁺ = 635 +++ 146 385

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.38 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H),7.21-7.08 (m, 2H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 6.94 (dd, J = 7.4,2.2 Hz, 1H), 4.09 (s, 2H), 3.13 (d, J = 6.9 Hz, 2H), 1.97 (tt, J = 8.5,5.2 Hz, 1H), 1.18-1.04 (m, 1H), 0.94-0.83 (m, 2H), 0.54-0.40 (m, 2H),0.36-0.25 (m, 2H), 0.26-0.15 (m, 2H); (M + H)⁺ = 571 +++ 146 386

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.47 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.30-7.14 (m, 2H), 7.12- 6.98 (m, 2H), 4.11 (s, 2H), 3.14 (d, J = 6.9 Hz,2H), 2.44 (d, J = 1.6 Hz, 2H), 1.11 (ddt, J = 10.3, 7.7, 2.9 Hz, 1H),0.80-0.75 (m, 9H), 0.36-0.25 (m, 2H), 0.27-0.15 (m, 2H); (M + H)⁺ = 601+++ 146 387

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.84 (s, 1H), 8.30 (s, 1H),7.69-7.56 (m, 3H), 7.58 (s, 2H), 7.56-7.49 (m, 4H), 7.39 (dd, J = 10.6,8.5 Hz, 1H), 7.16 (dd, J = 11.4, 1.5 Hz, 1H), 7.06 (dd, J = 8.1, 1.6 Hz,1H), 4.39 (s, 2H), 4.16 (s, 2H), 3.95 (d, J = 12.9 Hz, 2H), 3.60 (t, J =11.9 Hz, 2H), 3.26 (s, 1H), 3.17 (d, J = 6.8 Hz, 2H), 3.07 (s, 1H),1.22-1.04 (m, 1H), 0.38-0.29 (m, 2H), 0.26-0.17 (m, 2H); (M + H)⁺ = 706+++ 146 388

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.43 (ddd, J = 10.1, 5.8, 2.4 Hz, 2H), 7.24-7.09 (m, 2H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 4.14 (s, 2H), 3.17 (d, J =6.9 Hz, 2H), 2.72-2.56 (m, 3H), 2.36-2.17 (m, 2H), 1.65-1.39 (m, 5H),1.25-1.05 (m, 1H), 0.40-0.30 (m, 2H), 0.26-0.18 (m, 2H); (M + H)⁺ = 655+++ 146 389

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.74-7.61 (m, 2H), 7.58-7.44(m, 2H), 7.37 (dd, J = 10.7, 8.6 Hz, 1H), 7.31 (ddt, J = 10.3, 2.9, 1.5Hz, 1H), 7.29-7.17 (m, 2H), 7.17-7.04 (m, 2H), 4.18 (s, 2H), 3.17 (d, J= 6.9 Hz, 2H), 2.32 (s, 3H), 1.21-1.06 (m, 1H), 0.38-0.26 (m, 2H),0.28-0.17 (m, 2H); (M + H)⁺ = 638 ++ 141 390

(M + H)⁺ = 628 +++ 146 391

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.45 (ddd, J = 8.5, 5.0, 2.2 Hz, 1H), 7.31(dd, J = 7.3, 2.3 Hz, 1H), 7.23- 7.09 (m, 2H), 7.03 (dd, J = 8.1, 1.6Hz, 1H), 4.12 (s, 2H), 3.89 (dt, J = 11.3, 2.9 Hz, 2H), 3.39 (td, J =11.2, 3.5 Hz, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.98 (tt, J = 10.2, 5.0 Hz,1H), 1.50 (td, J = 11.4, 10.3, 4.0 Hz, 4H), 1.25-1.00 (m, 1H), 0.38-0.29 (m, 2H), 0.30-0.17 (m, 2H); (M + H)⁺ = 615 +++ 146 392

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.57(s, 2H), 7.24 (dd, J = 8.3, 7.6 Hz, 1H), 7.15 (dd, J = 11.3, 1.6 Hz,1H), 7.05 (dd, J = 8.2, 1.6 Hz, 1H), 7.03- 6.92 (m, 2H), 6.85 (t, J =1.9 Hz, 1H), 4.10 (s, 2H), 3.48-3.3 (m, 1H), 3.14 (d, J = 6.9 Hz, 2H),2.68- 2.53 (m, 2H), 2.47-2.27 (m, 2H), 1.80 (d, J = 12.4 Hz, 2H), 1.45(qd, J = 12.4, 4.0 Hz, 2H), 1.19-1.04 (m, 1H), 0.36-0.28 (m, +++ 1452H), 0.23-0.16 (m, 2H); (M + H)⁺ = 664 393

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.72-7.64 (m, 2H), 7.68-7.54(m, 2H), 7.59 (s, 2H), 7.55-7.30 (m, 6H), 7.21 (dd, J = 11.4, 1.6 Hz,1H), 7.10 (dd, J = 8.1, 1.6 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.18 (s,2H), 3.29 (s, 2H), 3.18 (d, J = 6.9 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H),1.23-1.08 (m, 1H), 0.39- 0.28 (m, 2H), 0.32- 0.21 (m, 2H); (M + H)⁺ =617 − 141 394

1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.27 (s, 1H), 7.67 (t, J =7.9 Hz, 1H), 7.59 (s, 2H), 7.25 (dd, J = 8.3, 7.6 Hz, 1H), 7.16 (dd, J =11.4, 1.6 Hz, 1H), 7.10-6.96 (m, 3H), 6.87 (dd, J = 2.6, 1.5 Hz, 1H),4.10 (s, 2H), 3.18-3.09 (m, 6H), 1.95 (tt, J = 14.1, 5.7 Hz, 4H),1.23-1.00 (m, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m, 2H); (M + H)+ = 632+++ 141 395

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.26 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 11.3,1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.90 (dt, J = 7.7, 1.1 Hz,1H), 6.70-6.50 (m, 2H), 4.12 (s, 2H), 3.59 (t, J = 13.3 Hz, 2H),3.4-3.29 (m, 2H), 2.31-2.29 (m, 2H), 3.14 (d, J = 6.9 Hz, 2H), 1.21-1.02(m, 1H), 0.38- 0.26 (m, 2H), 0.24-0.14 (m, 2H); (M + H)⁺ = 618 + 141 396

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.56(s, 2H), 7.29- 7.20 (m, 1H), 7.13 (dd, J = 11.4, 1.6 Hz, 1H), 7.08-6.90(m, 4H), 4.11 (s, 2H), 3.36 (d, J = 12.8 Hz, 1H), 3.13 (d, J = 6.9 Hz,2H), 2.68 (dd, J = 12.1, 11.0 Hz, 1H), 2.62-2.49 (m, 3H), 2.01-1.75 (m,0H), 1.69 (d, J = 12.9 Hz, 1H), 1.57-1.32 (m, 3H), 1.19-1.04 (m, 1H),0.36-0.27 (m, 2H), 0.24-0.15 (m, 2H); (M + H)⁺ = 664 +++ 141 397

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.27 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.24 (dd, J = 8.2, 7.6 Hz, 1H), 7.18-6.94 (m,4H), 6.89 (dd, J = 2.6, 1.5 Hz, 1H), 4.11 (s, 2H), 3.37 (t, J = 11.9 Hz,2H), 3.19-3.08 (m, 2H), 3.00 (t, J = 5.5 Hz, 2H), 1.98 (tt, J = 13.8,6.4 Hz, 2H), 1.72-1.52 (m, 2H), 1.18-1.04 (m, 1H), 0.37-0.25 (m, 2H),0.25-0.16 (m, 2H); (M + H)⁺ = 632 +++ 141 398

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.77 (d, J= 1.8Hz, 1H), 7.68-7.57 (m, 2H), 7.57-7.50 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H),7.12-6.99 (m, 2H), 6.11 (s, 1H), 4.12 (s, 1H), 3.14 (d, J = 6.8 Hz, 2H),1.39 (tt, J = 8.4, 5.3 Hz, 1H), 1.18-1.04 (m, 1H), 0.70 (dq, J = 10.0,5.1 Hz, 1H), 0.54-0.42 (m, 1H), 0.37-0.09 (m, 5H); (M + H)⁺ = 651 +++141 399

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.21 (s, 1H), 7.70-7.63 (m,2H), 7.63-7.56 (m, 1H), 7.56 (s, 2H), 7.49- 7.36 (m, 2H), 7.06- 6.95 (m,2H), 6.03 (s, 1H), 3.85 (s, 2H), 2.42 (d, J = 6.8 Hz, 2H), 1.48 (tt, J =8.3, 5.3 Hz, 1H), 1.01- 0.86 (m, 2H), 0.67 (dq, J = 10.0, 5.1Hz, 1H),0.49-0.33 (m, 4H), 0.27-0.04 (m, 5H); (M + H)⁺ = 651 + 141 400

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.31-7.09 (m, 4H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 4.16-4.05 (m, 3H), 3.85 (ddd, J = 10.6, 8.6, 1.6 Hz, 1H), 3.15 (d,J = 6.7 Hz, 2H), 2.29-1.99 (m, 0H), 1.70 (tdd, J = 12.0, 8.0, 4.9 Hz,2H), 1.43 (dtd, J = 13.8, 7.8, 4.2 Hz, 1H), 1.26-0.93 (m, 1H), 0.37-0.16(m, 4H); (M + H)⁺ = 637 +++ 120 401

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.68-7.46 (m,5H), 7.28 (dd, J = 9.5, 8.7 Hz, 1H), 7.12 (dd, J = 11.3, 1.6 Hz, 1H),7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.14 (d, J = 6.2 Hz, 3H),2.07 (s, 3H), 1.11 (dddd, J = 12.5, 8.0, 4.9, 1.9 Hz, 1H), 0.37-0.27 (m,2H), 0.27-0.16 (m, 2H); (M + H)⁺ = 569 +++ 145 402

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.69-7.44 (m,6H), 7.27 (dd, J = 9.4, 8.7 Hz, 1H), 7.15 (dd, J = 11.4, 1.6 Hz, 1H),7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13 (s, 2H), 3.16 (d, J = 6.8 Hz, 2H),1.27 (s, 9H), 1.18-0.96 (m, 1H), 0.37-0.27 (m, 2H), 0.27-0.16 (m, 2H);(M + H)⁺ = 611 +++ 145 403

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.29 (s, 1H), 7.78-7.68 (m,2H), 7.68-7.58 (m, 2H), 7.56 (s, 2H), 7.47 (dd, J = 3.7, 1.2 Hz, 1H),7.37 (dd, J = 9.4, 8.7 Hz, 1H), 7.19- 7.11 (m, 2H), 7.04 (dd, J = 8.1,1.6 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.20-1.05 (m, 1H),0.38-0.27 (m, 2H), 0.27-0.17 (m, 2H); (M + H)⁺ = 637 +++ 145 404

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.27 (s, 1H), 7.68-7.56 (m,3H), 7.56 (s, 1H), 7.38- 7.29 (m, 1H), 7.13 (dd, J = 11.3, 1.5 Hz, 1H),7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.34 (s, 2H), 4.14 (s, 2H), 3.31 (s,3H), 3.15 (d, J = 6.5 Hz, 2H), 1.33- 0.83 (m, 0H), 0.37- 0.27 (m, 2H),0.24- 0.16 (m, 2H); (M + H)⁺ = 599 +++ 145 405

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H),7.74- 7.60 (m, 3H), 7.57 (s, 2H), 7.43-7.34 (m, 2H), 7.16 (dd, J = 11.3,1.6 Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.16 (s, 2H), 3.67 (d, J =0.5 Hz, 3H), 3.16 (d, J = 6.9 Hz, 2H), 1.26-0.96 (m, 1H), 0.38-0.28 (m,2H), 0.25-0.17 (m, 2H); (M + H)⁺ = 635 +++ 145 406

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (s, 1H), 7.82 (d, J =8.1 Hz, 1H), 7.52 (s, 2H), 7.42- 7.31 (m, 2H), 7.21- 7.11 (m, 2H), 6.94(dd, J = 7.4, 2.2 Hz, 1H), 4.08 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 1.97(tt, J = 8.4, 5.2 Hz, 1H), 1.19-1.04 (m, 2H), 0.96-0.83 (m, 2H),0.54-0.40 (m, 2H), 0.37-0.26 (m, 2H), 0.26- 0.15 (m, 2H); (M + H)⁺ = 588+++ 146 407

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.28 (s, 1H), 7.85 (d, J =8.2 Hz, 1H), 7.61-7.43 (m, 6H), 7.35 (dd, J = 11.3, 8.6 Hz, 1H),7.22-7.10 (m, 2H), 6.82 (dt, J = 3.6, 1.1 Hz, 1H), 4.15 (s, 2H), 3.17(d, J = 6.9 Hz, 2H), 1.20-0.98 (m, 1H), 0.38-0.29 (m, 2H), 0.28-0.17 (m,2H); (M + H)⁺ = 644 +++ 145 408

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.72 (dd, J =6.9, 2.3 Hz, 1H), 7.68-7.58 (m, 2H), 7.56 (s, 2H), 7.36 (dd, J = 9.4,8.7 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 7.14 (dd, J = 11.3, 1.6 Hz, 1H),7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.83 (dt, J = 3.4, 1.1 Hz, 1H), 4.16 (s,2H), 3.16 (d, J = 6.9 Hz, 2H), 1.20- 1.05 (m, 1H), 0.38- 0.27 (m, 2H),0.27- 0.16 (m, 2H); (M + H)⁺ = 651 +++ 145 409

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68-7.57 (m, 2H), 7.56 (s,2H), 7.52 (ddd, J = 8.7, 5.0, 2.3 Hz, 1H), 7.28 (dd, J = 9.4, 8.7 Hz,1H), 7.12 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H),4.89 (d, J = 6.3 Hz, 1H), 4.13 (s, 2H), 3.57 (q, J = 6.6 Hz, 2H), 3.15(d, J = 6.7 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.11 (dddd, J = 15.0,10.0, 5.0, 2.2 Hz, 1H), 0.37-0.27 (m, 2H), 0.24- 0.16 (m, 2H); (M + H)⁺= 599 +++ 145 410

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.72-7.57 (m,3H), 7.55 (s, 2H), 7.33 (t, J = 9.0 Hz, 1H), 7.12 (dd, J= 11.4, 1.6 Hz,1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.53 (s, 1H), 4.14 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 1.18-1.04 (m, 1H), 0.37-0.27 (m, 2H), 0.24-0.16 (m,2H); M + H)⁺ = 556 +++ 145 411

(M + H)⁺ = 637 +++ 145 412

¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.68-7.51 (m, 4H), 7.30 (dd, J= 9.4, 8.6 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.1,1.6 Hz, 1H), 5.39 (s, 1H), 4.13 (s, 2H), 3.18-3.11 (m, 2H), 1.96-1.79(m, 4H), 1.79-1.59 (m, 4H), 1.10 (s, 1H), 0.36- 0.15 (m, 4H); (M + H)⁺ =639 +++ 145 413

(M + H)⁺ = 641 +++ 145 414

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.30 (s, 1H), 7.76 (dd, J =6.7, 2.3 Hz, 1H), 7.72-7.58 (m, 2H), 7.57 (s, 2H), 7.39 (t, J = 9.0 Hz,1H), 7.14 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H),4.99-4.81 (m, 4H), 4.15 (s, 2H), 3.16 (d, J = 7.2 Hz, 2H), 1.20-1.05 (m,1H), 0.38-0.27 (m, 2H), 0.27-0.17 (m, 2H); (M + H)⁺ = 629 +++ 145 415

¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.74-7.53 (m, 4H), 7.39-7.26(m, 1H), 7.13 (dd, J = 11.4, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 6.69 (s, 1H), 4.78-4.71 (m, 2H), 4.62-4.55 (m, 2H), 4.15 (s, 2H),3.15 (d, J = 6.5 Hz, 2H), 1.18- 1.03 (m, 1H), 0.37- 0.25 (m, 2H), 0.25-0.13 (m, 2H); (M + H)⁺ = 627 +++ 145 416

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.68-7.58 (m,2H), 7.58-7.54 (m, 3H), 7.36-7.26 (m, 1H), 7.15 (dd, J = 11.3, 1.6 Hz,1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H), 4.43 (d,J = 5.7 Hz, 2H), 4.14 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.62 (s, 3H),1.12 (s, 1H), 0.38- 0.28 (m, 2H), 0.25- 0.17 (m, 2H); (M + H)⁺ = 625 +++145 417

¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.36 (s, 1H), 8.32 (s, 1H),7.79- 7.55 (m, 5H), 7.40 (t, J = 9.0 Hz, 1H), 7.14 (dd, J= 11.3, 1.6 Hz,1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.40 (s, 2H), 4.16 (s, 2H), 3.17(d, J = 6.9 Hz, 2H), 1.96 (s, 4H), 1.23-1.00 (m, 0H), 0.39-0.29 (m, 2H),0.26-0.18 (m, 2H); (M + H)⁺ = 638 +++ 145 418

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.27 (s, 1H), 7.68-7.58 (m,3H), 7.57 (d, J = 4.7 Hz, 2H), 7.37-7.27 (m, 1H), 7.13 (dd, J = 11.5,1.5 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 5.92 (s, 1H), 4.14 (s, 2H),3.91- 3.83 (m, 2H), 3.83- 3.72 (m, 2H), 3.15 (d, J = 6.7 Hz, 2H), 2.24-2.13 (m, 2H), 0.98 (s, 1H), 0.57 (s, 1H), 0.37-0.28 (m, 2H), 0.25-0.16(m, 2H); (M + H)⁺ = 641 +++ 145 419

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.72-7.59 (m,3H), 7.57 (s, 2H), 7.37 (t, J = 9.3 Hz, 1H), 7.15 (dd, J = 11.4, 1.6 Hz,1H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.23- 4.10 (m, 3H), 4.00- 3.85 (m,3H), 3.16 (d, J = 7.0 Hz, 2H), 2.61-2.33 (m, 13H), 1.12 (dddd, J = 13.0,8.0, 4.9, 1.9 Hz, 1H), 0.38-0.17 (m, 4H); (M + H)⁺ = 643 +++ 145 420

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H),7.61-7.54 (m, 3H), 7.51 (ddd, J = 8.6, 5.0, 2.3 Hz, 1H), 7.28 (dd, J =9.4, 8.7 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2,1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.07(s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.18-1.07 (m, 1H), 0.38-0.29 (m, 2H),0.25-0.17 (m, 2H); (M + H)⁺ = 597 + 145 421

(M + H)⁺ = 639 +++ 145 422

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.65-7.38 (m,5H), 7.34-7.21 (m, 4H), 4.11 (s, 2H), 3.14 (dd, J = 5.8, 3.3 Hz, 2H),2.06 (s, 3H), 1.17-1.03 (m, 1H), 0.36-0.25 (m, 2H), 0.25-0.14 (m, 2H);(M + H)⁺ = 551 +++ 145 423

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.51 (m, 4H), 7.34-7.24 (m, 1H), 7.14 (dd, J = 11.4,1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13 (s, 2H), 3.95 (dd, J =8.1, 7.3 Hz, 1H), 3.87-3.68 (m, 2H), 3.58 (dd, J = 8.1, 6.5 Hz, 1H),3.34- 3.22 (m, 6H), 3.15 (d, J = 6.9 Hz, 2H), 2.25 (dddd, J = 12.1, 8.5,7.4, 6.0 Hz, 1H), 1.92 (ddt, J = 12.1, 7.8, 6.6 Hz, 1H), 1.12 (s, 1H),0.37-0.28 (m, 2H), 0.25-0.16 (m, 2H); M + H)⁺ = 625 +++ 145 424

¹H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.14 (s, 1H), 7.80 (d, J =8.2 Hz, 2H), 7.05 (s, 2H), 5.96 (s, 1H), 3.81 (s, 3H); (M + H)⁺ = 318 −147 425

(M + H)+ = 306 − 147 426

¹H NMR (400 MHz, DMSO-d 6.09-7.99 (m, 2H), 7.92 (s, 1H), 7.41-7.30 (m,2H); (M + H)⁺ = 358 + 150 427

¹H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.40 (s, 1H), 8.05-7.93 (m,4H), 7.63-7.52 (m, 2H); (M + H)⁺ = 374 + 150 428

¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 0.5 Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.57-7.44 (m, 4H), 7.37-7.31 (m, 2H), 7.13 (dd, J = 11.3, 1.5Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.13(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.82 (p, J = 7.3 Hz, 1H), 2.00-1.87(m, 2H), 1.75-1.47 (m, 6H), 1.35-1.28 (m, 2H), 1.26 (d, J = 19.9 Hz,1H), 1.18-1.07 (m, 1H), 0.38-0.28 (m, 2H), 0.28-0.19 (m, 2H); (M + H)⁺ =633 − 145 429

(M + H)⁺ = 633 + 145 430

(M + H)⁺ = 605 +++ 145 431

(M + H)⁺ = 609 +++ 145 432

(M + H)⁺ = 605 +++ 145 433

(M + H)⁺ = 577 +++ 145 434

(M + H)⁺ = 637 + 145 435

(M + H)⁺ = 605 + 145 436

(M + H)⁺ = 641 +++ 145 437

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.50 (m, 4H), 7.29 (dd, J = 9.4, 8.5 Hz, 1H), 7.13(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s,2H), 3.14 (d, J = 6.9 Hz, 2H), 2.51 (d, J = 5.9 Hz, 2H), 1.11 (dddd, J =15.0, 10.0, 5.1, 2.2 Hz, 1H), 1.05- 0.92 (m, 1H), 0.51-0.41 (m, 2H),0.37-0.28 (m, 2H), 0.27-0.16 (m, 4H); (M + H)⁺ = 609 +++ 145 438

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.28 (s, 1H), 7.61 (dt, J =7.9, 1.4 Hz, 1H), 7.56-7.38 (m, 4H), 7.32 (dt, J = 7.7, 1.4 Hz, 1H),7.27 (s, 2H), 7.24 (d, J = 8.9 Hz, 1H), 4.10 (s, 2H), 3.15 (d, J = 6.8Hz, 2H), 2.87 (p, J = 7.2 Hz, 1H), 2.02- 1.49 (m, 8H), 1.10 (tdd, J =12.0, 7.1, 2.4 Hz, 1H), 0.37-0.27 (m, 2H), 0.23-0.14 (m, 2H); (M + H)⁺ =605 ++ 145 439

(M + H)⁺ = 641 ++ 145 440

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.83 (dd, J =6.7, 2.3 Hz, 1H), 7.72 (ddd, J = 8.7, 5.1, 2.3 Hz, 1H), 7.62 (t, J = 7.9Hz, 1H), 7.55 (s, 2H), 7.42 (t, J = 9.1 Hz, 1H), 7.15-7.07 (m, 1H),7.06-6.97 (m, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.18-1.02 (m,1H), 0.36-0.28 (m, 2H), 0.24-0.17 (m, 2H); (M + H)+ = 606 +++ 145 441

¹H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H),7.51 (dd, J = 6.8, 2.3 Hz, 1H), 7.33 (ddd, J = 8.6, 4.9, 2.3 Hz, 1H),7.08- 6.90 (m, 3H), 5.30 (s, 2H), 5.10 (s, 2H), 4.99 (s, 2H), 4.05 (s,2H), 3.18 (d, J = 6.8 Hz, 2H), 2.85 (p, J = 7.4 Hz, 1H), 2.25 (s, 3H),2.12-1.93 (m, 1H), 1.86-1.54 (m, 7H), 1.17-1.02 (m, 1H), 0.47-0.39 (m,2H), 0.28-0.22 (m, 2H); (M + H)⁺ = 735 − 145 442

(M + H)⁺ = 580 +++ 145 443

¹H NMR (400 MHz, DMSO-d6) δ 13.34- 12.89 (m, 1H), 8.29 (s, 1H),7.71-7.58 (m, 3H), 7.56 (s, 2H), 7.36 (t, J = 8.9 Hz, 1H), 7.18-6.96 (m,2H), 5.77-5.53 (m, 1H), 4.14 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.60(dd, J = 23.0, 6.5 Hz, 3H), 1.12 (tq, J = 9.8, 3.4, 2.4 Hz, 1H), 0.38-0.28 (m, 2H), 0.25- 0.16 (m, 2H); (M + H)⁺ = 601 +++ 145 444

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.35 (dd, J = 7.6, 2.3 Hz, 1H), 7.29-7.01 (m,3H), 6.25 (p, J = 2.1 Hz, 1H), 4.12 (s, 2H), 3.18-3.11 (m, 2H),2.49-2.38 (m, 4H), 1.85 (p, J = 7.6 Hz, 2H), 1.12 (tdd, J = 11.3, 6.4,2.0 Hz, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ = 597 +++145 445

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.48 (m, 4H), 7.28 (t, J = 9.0 Hz, 1H), 7.14 (dd, J =11.4, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.12 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 2.82 (hept, J = 6.8 Hz, 1H), 1.20 (d, J = 6.9 Hz,6H), 1.12 (tq, J = 9.9, 3.5, 2.2 Hz, 1H), 0.38-0.28 (m, 2H), 0.25-0.17(m, 2H); (M + H)⁺ = 597 +++ 145 446

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.58-7.49 (m, 4H), 7.28 (dd, J = 9.5, 8.3 Hz, 1H), 7.14(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s,2H), 3.36-3.23 (m, 1H), 3.15 (d, J = 6.6 Hz, 2H), 2.34- 2.23 (m, 2H),2.19- 2.07 (m, 2H), 2.01- 1.81 (m, 2H), 1.19- 1.04 (m, 1H), 0.37- 0.28(m, 2H), 0.25- 0.16 (m, 2H); (M + H)+ = 609 +++ 145 447

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.72 (dd, J = 6.9, 2.3 Hz,1H), 7.69- 7.51 (m, 4H), 7.36 (t, J = 9.0 Hz, 1H), 7.27 (d, J = 3.6 Hz,1H), 7.15 (dd, J = 11.3, 1.6 Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H),6.83 (dt, J = 3.6, 1.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H),3.16 (d, J = 6.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.19-1.04 (m, 1H),0.40-0.29 (m, 2H), 0.27-0.19 (m, 2H); (M + H)⁺ = 679 − 145 448

(M + H)⁺ = 613 +++ 145 449

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.69-7.60 (m,2H), 7.59-7.47 (m, 4H), 7.42 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 3.6 Hz,1H), 7.14 (dd, J = 11.3, 1.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H),6.81 (dd, J = 3.6, 1.3 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.1 Hz, 2H),2.47- 2.44 (m, 3H), 1.13 (dqd, J = 14.8, 7.2, 5.0 Hz, 1H), 0.38- 0.28(m, 2H), 0.26- 0.15 (m, 2H); (M + H)⁺ = 633 +++ 145 450

(M + H)⁺ = 585 +++ 145 451

2-(5-hydroxy-3- (naphthalen-2-yl)-4- (4-sulfamoylbenzyl)- ¹H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.19 (s, 1H), 8.09(d, 2H, J = 1.6 Hz), 8.00 (d, 1H, J = 8 Hz), 7.86 (d, 1H, J = 8 Hz)7.63-7.51 (m, 6H), 7.12 (d, 1H, J = 8 Hz), 3.69 (s, 2H); MS (ES) 506.9(M + H)⁺ LCMS RT = 0.88 min. + Example 69 452

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.18(s, 1H), 7.85 (d, 2H, J = 8.4 Hz), 7.56 (m, 1H), 7.45-7.41 (m, 4H), 3.99(s, 2H); MS (ES) 492.9 (M + H)⁺ LCMS RT = 0.88 min. ++ Example 70 453

2-(5-hydroxy-3- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA: VU0657478 (PC-6- 098); MS (ES)457.9 (M + H)⁺ LCMS RT = 0.30 min. + Example 71 454

2-(3-(6- fluoronaphthalen-1- (57%) yl)-5-hydroxy- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.20(m, 2H), 7.88 (d, 2H, J = 8 Hz), 7.70- 7.55 (m, 5H), 7.32 (m, 1H), 7.12(d, 1H, J = 8 Hz), 3.69 (s, 2H); MS (ES) 524.9 (M + H)⁺ LCMS RT = 0.94min. + Example 72 455

2-(3-(3,4- difluorophenyl)-5- methoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.20(s, 1H), 7.81 (d, 2H, J = 8 Hz), 7.54- 7.50 (m, 2H), 7.39- 7.36 (m, 3H),3.69 (s, 2H), 3.49 (s, 3H); MS (ES) 506.9 (M + H)⁺ LCMS RT = 0.89 min.++ Example 73 456

2-(3-(6-fluoro-3′- methoxy-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)565.0 (M + H)⁺ LCMS RT = 1.08 min. +++ Example 85 457

2-(3-(3′-chloro-6- fluoro-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 568.9 (M + H)⁺LCMS RT = 1.16 min. +++ Example 86 458

2-(3-(3′,6-difluoro- [1,1′-biphenyl]-3-yl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 552.9 (M + H)⁺LCMS RT = 1.12 min. +++ Example 87 459

2-(3-(3-isopropoxy- phenyl)-4-(4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H-NMR (d6- DMSO) δ 8.24 (m, 2H), 7.78(d, 2H, J = 8 Hz), 7.44 (d, 2H, J = 8 Hz), 7.39-7.30 (m, 3H), 7.22 (d,1H, J = 8 Hz), 7.09 (d, 1H, J = 4 Hz), 6.99- 6.96 (m, 1H), 4.51 (m, 1H),4.15 (s, 2H), 1.27 (d, 6H, J = 8 Hz); MS (ES) 499.0 (M + H)⁺ LCMS RT =1.07 min. +++ Example 74 460

2-(3-(3-(cyclopentyl- oxy)phenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.55 (m,2H), 8.25 (d, 2H, J = 4 Hz), 7.77 (d, 2H, J = 4 Hz), 7.55-7.26 (m, 3H),7.22 (d, 1H, J = 8 Hz), 7.09 (d, 1H, J = 8 Hz), 6.99-6.96 (m, 1H), 4.74(m, 1H), 4.15 (s, 2H), 1.91-1.82 (m, 2H), 1.69- 1.58 (m, 4H), 1.23 (m,2H); MS (ES) 525.0 (M + H)⁺ LCMS +++ Example 75 RT= 1.15 min. 461

2-(4-(4- sulfamoylbenzyl)-3- (3-((tetrahydrofuran- 3-yl)methoxy)phenyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS(ES) 540.7 (M + H)⁺ LCMS RT = 1.13 min. +++ Example 76 462

2-(3-(3-((3- methoxybenzyl)oxy) phenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 576.9 (M + H)⁺LCMS RT = 1.02 min. +++ Example 77 463

2-(4-(4- sulfamoylbenzyl)-3- (3-((tetrahydrofuran- 2-yl)methoxy)phenyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS(ES) 540.9 (M + H)⁺ LCMS RT = 0.76 min. +++ Example 78 464

2-(3-(3- phenoxyphenyl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid; MS (ES) 532.9 (M + H)⁺ LCMS RT = 0.98min. +++ Example 79 465

2-(3-(3-(pyridin-3- ylmethoxy)phenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid, TFA MS (ES) 548.0 (M + H)⁺LCMS RT = 0.68 min. +++ Example 80 466

2-(3-(3-(pyridin-2- ylmethoxy)phenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid TFA; MS (ES) 547.9 (M +H)⁺, LCMS RT = 0.68 min. +++ Example 81 467

Synthesis of 2-(3-(3- (cyclopentyloxy)-4- methylphenyl)-5-(cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H-NMR (d6- DMSO) δ 8.07 (s, 1H), 7.53(d, 2H, J = 8 Hz), 7.12-7.07 (m, 5H), 6.95 (d, 1H, J = 8 Hz), 6.87 (d,1H, J = 8 Hz), 6.63 (s, 1H), 4.16 (m, 1H), 3.90 (s, 2H), 2.93 (m, 2H),1.87 (s, 3H), 1.40- 1.29 (m, 8H), 0.91 (m, +++ Example 120 1H), 0.11 (m,2H), 0.014 (m, 2H); MS (ES) 593.4 (M + H)⁺, LCMS RT = 0.81 min. 468

2-(3-(5-(cyclopentyl- oxy)-2-fluorophenyl)-5- (cyclopropylmethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid;¹H-NMR (d6-DMSO) δ 8.07 (s, 1H), 7.43 (d, 2H, J = 8 Hz), 7.02-6.93 (m,5H), 6.73 (m, 1H), 6.60 (m, 1H), 4.40 (m, 1H), 2.93 (m, 2H), 1.59-1.54(m, 2H), 1.52-1.32 (m, 6H), 0.91 (m, 1H), 0.013 (m, 2H), 0.010 (m, 2H);MS (ES) 597.4 (M + H)⁺, LCMS RT = 067 min. ++ By analogy with Example120 469

2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- ((tetrahydrofuran-2-yl)methoxy)phenyl)-4- (3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazo1e-4-carboxylic acid; ¹H-NMR (d6- DMSO) δ 8.07 (s, 1H), 7.44(m, 1H), 7.35 (s, 2H), 7.05-6.82 (m, 5H), 3.93 (s, 2H), 3.87-3.43 (m,6H), 2.93 (m, 2H). 1.75-159 (m, 3H), 1.38 (m, 1H), 0.90 (m, 1H), 0.013(m, 2H) 0.010 (m, 2H); MS (ES) 630.9 (M + H)⁺, LCMS RT = 1.10 min. +++Example 121 470

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-((tetrahydro-furan-3-yl)methoxy) phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H-NMR (d6-DMSO) δ 8.07 (s,1H), 7.44 (m, 1H), 7.35 (s, 2H), 7.04-7.01 (m, 1H), 6.95- 6.91 (m, 3H),6.84-6.82 (m, 1H), 3.92 (s, 2H), 3.52-3.50 (m, 4H), 3.40- 3.35 (m, 2H),3.20 (m, 1H), 2.93 (m, 2H), 2.4 (m, 1H), 1.77 (m, 1H), 1.39 (m, 1H),0.91 (m, 1H), 0.013 (m, 2H) 0.010 (m, 2H); MS (ES) 552.9 (M + H)⁺, LCMSRT = 1.12 min. +++ Example 122 471

2-(3-(3-cyclopropoxy- 4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylicacid; ¹H-NMR (d6- DMSO) δ 8.07 (s, 1H), 7.46 (m, 1H), 7.37 (s, 2H), 7.19(m, 1H), 7.05-6.85 (m, 5H), 3.92 (s, 2H), 3.50 (m, 1H), 2.93 (m, 2H),0.91 (m, 1H), 0.013 (m, 2H) 0.010 (m, 2H); MS (ES) 586.9 (M + H)⁺, LCMSRT = 1.12 min. +++ Example 123 472

2-(5-(cyclopropyl- methyl)-3-(6-fluoro-4- methyl-[1,1′-biphenyl]-3-yl)-4-(2-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.31 (s, 1H), 7.59-7.35 (m, 11H),7.17 (m, 1H), 4.13 (s, 2H), 3.02 (m, 2H), 2.35 (s, 3H), 1.15 (m, 1H),0.033 (m, 2H) 0.021 (m, 2H); MS (ES) 621.4 (M + H)⁺, LCMS RT = 0.79 min.Example 124 473

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((5- (trifluoro-methyl)furan-2- yl)methoxy)phenyl)- 4-(3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 694.9 (M + H)⁺,LCMS RT = 1.20 min. +++ Example 125 474

2-(5-(naphthalen-2- yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.24 (s, 1H), 8.13(s, 1H), 7.91-8.03 (m, 4H), 7.80 (d, J = 8.2 Hz, 2H), 7.52- 7.58 (m,3H), 7.32 (s, 2H), 4.25 (s, 2H); MS (ES) 491 (M + H)⁺ LCMS RT 1.04 min.+++ Example 82 475

2-(5-(pyridin-3-yl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid; MS (ES) 442 (M + H)⁺ LCMS RT 0.64 min. ++ Example 83476

2-(3-(6-fluoro-4- methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.27(d, J = 9.24 Hz, 2H), 7.76-7.78 (m, 4H), 7.29-7.46 (m, 8H), 4.2 (s, 2H),2.35 (s, 3H); MS (ES) 549 (M + H)⁺ LCMS RT 1.27 min. +++ Example 84 477

2-(3-(3-(cyclo- pentyloxy)phenyl)-5- (cyclopropylmethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H-NMR (CDCl₃) δ 8.10 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.23- 7.31 (m,4H), 7.02- 7.07 (m, 2H), 6.88 (dd, J = 1.76, 1.8 Hz, 1H) 4.97 (s, 2H),4.11 (s, 2H), 3.15 (d, J = 6.64 Hz, 2H), 1.58- 1.79 (m, 9H), 1.12- 1.16(m, 1H), 0.43 (d, J = 8 Hz, 2H), 0.21 (d, J = 5.4 Hz, 2H), MS (ES) 579(M + H)⁺ LCMS RT 1.15 min. Example 126 478

2-(5-(cyclopropyl- methyl)-3-(5-fluoro-3′- methoxy-[1,1′-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid; ¹H- NMR (CDCl₃) δ 8.10 (s, 1H) 7.86 (d, J = 8.32 Hz,2H,) 7.23- 7.29 (m, 7H), 7.00 (d, J = 7.12 Hz, 1H), 6.91 (dd, J = 1.881.88 Hz, 1H), 6.60 (t, J = 3.92 Hz, 1H), 4.96 (s, 2H), 4.11 (s, 2H), ),3.87 (s, 3H), 3.21 (d, J = 6.64 Hz, 2H) 1.17-1.25 (m, 1H) 0.47 (d, J =7.28 Hz, 2H), 0.24 (d, J = 5.2 Hz, 2H), MS: (ES) 619 (M + H)⁺ LCMS RT1.32 min. +++ Example 143 479

2-(5- (cyclopropylmethyl)- 3-(4′,5-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)607 (M + H)⁺ LCMS RT 1.35 min. +++ Example 144 480

2-(3-(3-(benzyloxy)- 4-fluorophenyl)-5- (cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR(CDCl₃) δ 8.11 (s, 1H), 7.84 (d, J = 8 Hz, 2H), 7.24- 7.38 (m, 8H), 7.15(d, J = 7.4 Hz, 1H) 7.08 (d, J = 8 Hz, 2H), 5.01 (s, 2H), 4.95 (s, 3H),4.02 (s, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.11-1.15 (m, 1H), 0.42 (d, J =7 Hz, 2H), 0.21 (d, J = 5.24 Hz, 2H); MS (ES) 619 (M + H)⁺ LCMS RT =1.28 min. +++ Example 127 481

2-(5- (cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)- 3-(3-(4-(trifluoro-methyl)phenoxy) phenyl)-1H-pyrazol- 1-yl)thiazole- 4-carboxylic acid;¹H-NMR (CDCl₃) δ 8.11 (s, 1H), 7.8 (d, J = 8 Hz, 2H), 7.6 (d, J = 8 Hz,2H), 7.21- 7.40 (m, 5H), 7.01- 7.06 (m, 3H), 5.04 (s, 2H), 4.08 (s, 2H),3.16 (d, J = 6 Hz, 2H), 1.09-1.15 (m, 1H) 0.42 (d, J = 8. Hz, 2H), 0.21(d, J = 5 Hz, 2H), MS (ES) 655 (M + H)⁺ LCMS RT = 1.38 min in 2 minmethod. +++ Example 128 482

2-(5-cyclopropyl-3 - (4′,6-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR(MeOD): δ 8.27 (s, 1H) 7.85 (d, J = 12 Hz, 2H), ; 7.57-7.63 (m, 1H), 7.5(d, J = 16 Hz, 1H), 7.29-7.42 (m, 4H), 7.12-7.25 (m, 4H), 4.25 (s, 2H),2.32-2.41 (m, 1H), 1.15 (d, J = 12 Hz, 2H), 0.7 (d, J = 9 Hz, 2H); (ES)593 (M + H)⁺ LCMS RT = 1.28 min in 2 min method. +++ Example 112 483

2-(5-cyclopropyl-3- (6-fluoro-3′-methoxy- [1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid;¹H-NMR (CDCl₃) δ 8.13 (s, 1H), 7.85 (d, J = 8 Hz, 2H), 7.55-7.59 (m,1H), 7.35-7.39 (m, 2H), 7.25-7.31 (m, 4H), 7.17 (t, J = 18.84 Hz, 1H),7.04 (d, J = 7.56 Hz, 1H), 6.91-6.94 (dd, J = 2, 2 Hz, 1H), 6.73 (s,1H), 5.04 (s, Broad, 2H), 4.17 (s, 2H), 3.87 (s, 3H), 2.23-2.27 (m, 1H),1.12 (d, J = 7 Hz, 2H), 0.73 (d, J = 5 Hz, 2H), MS (ES) 605 (M + H)⁺LCMS RT = 1.25 min in 2 min method. +++ Example 113 484

2-(5-cyclopropyl-3- (6-fluoro-4′-methyl- [1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H-NMR (CDCl₃) δ 8.10 (s, 1H), 7.82 (d, J = 8. Hz, 2H), 7.5 (dd, J1 = 2; J2= 2 Hz, 1H), 7.41-7.45 (m, 1H), 7.22-7.32 (m, 7H), 7.13 (t, J = 19 Hz,1H), 5.06 (s, 2H), 4.14 (s, 2H), 2.40 (s, 3H), 2.17- 2.23 (m, 1H), 1.07(d, J = 8 Hz, 2H), 0.68 (d, J = 5. Hz, 2H), MS (ES) 589 (M + H)⁺ LCMS RT= 1.31 min in 2 min method. +++ Example 114 485

2-(5-(cyclopropyl- methyl)-3-(3-(phenyl- amino)phenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(CDCl₃) δ 7.96 (1H, s), 7.72 (2H, d, J = 8.3 Hz), 7.23-7.18 (6H, m),7.02-6.99 (4H, m), 6.88 (1H, t, J = 7.4 Hz), 4.02 (2H, s), 3.10 (2H, d,J = 6.8 Hz), 1.01 (1H, m), 0.33 (2H, dd, J = 13.8, 5.8 Hz), 0.14 (2H,dd, J = 10.2, 5.0 Hz); MS(ES) 587.7 (M + H)⁺; LCMS RT = 1.06 min. +++Example 115 486

2-(3-(4-methyl-3- (pyridin-3-yl)phenyl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.77 (s,1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H),7.92 (dd, J = 7.6, 5.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (dd, J =7.6, 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H),4.21 (s, 2H), 2.34 (s, 3H); MS (ES) 532.7 (M + H)⁺, LCMS RT = 0.82 min.+++ Example 88 487

2-(3-(3′-amino-6- methyl-[1,1′-biphenyl]-3- yl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid; ¹H-NMR (MeOD) δ8.37 (s, 1H), 8.16 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 7.6,6.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.40(s, 2H), 7.38 (s, 1H), 7.27-7.20 (m, 2H), 7.15 (s, 1H), 4.19 (s, 2H),2.30 (s, 3H); MS (ES) 546.7 (M + H)⁺; LCMS RT = 0.87 min. +++ Example 89488

2-(3-(3′-ethyl-6- methyl-[1,1′-biphenyl]-3- yl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid; ; ¹H-NMR (MeOD) δ8.34 (s, 1H), 8.13 (s, 1H), 7.83 (d,J = 8.4 Hz, 2H), 7.59 (dd, J = 8.0,2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.35(d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J= 8.0 Hz, 1H), 4.20 (s, 2H), 2.73 (q, J = 8.0 Hz, 2H), 2.29 (s, 3H),1.30 (t, J = 8.0 Hz, 3H); MS (ES) ++ Example 90 559.4 (M + H)⁺; LCMS RT= 1.28 min. 489

2-(3-(3′,5′-difluoro-6- methyl-[1,1′-biphenyl]-3- yl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 569.6 (M +H)⁺; LCMS RT = 1.24 min. ++ Example 91 490

2-(3-(4-methyl-3- (pyridin-4-y1)pheny1)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H- NMR (MeOD) δ 8.80 (brs, 2H), 8.44 (s, 1H), 8.17 (s, 1H), 7.85-7.76 (m, 5H), 7.49 (d, J = 6.0Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 4.21 (s,2H), 2.39 (s, 3H); MS (ES) 533.6 (M + H)⁺; LCMS RT = 0.83 min. ++Example 92 491

2-(3-(6-methyl- [1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H- NMR (MeOD) δ 8.34 (s,1H), 8.14 (s, 1H), 7.89-7.82 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.60(dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.49-7.35 (m, 4H),7.29 (d, J = 8.0 Hz, 2H), 4.20 (s, 2H), 2.30 (s, H); MS (ES) 531.6 (M +H)⁺; LCMS RT = 1.18 min. ++ Example 93 492

2-(3-(3′,4′-difluoro-6- methyl-[1,1′-biphenyl]- 3-yl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 567.9 (M +H)⁺; LCMS RT = 1.20 min. ++ Example 94 493

2-(3-(4′-fluoro-3′,6- dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)563.9 (M + H)⁺; LCMS RT = 1.25 min. ++ Example 95 494

2-(3-(3′-fluoro-4′- methoxy-6-methyl- [1,1′-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)579.6 (M + H)⁺; LCMS RT = 1.18 min. ++ Example 96 495

2-(4-(4- sulfamoylbenzyl)-3- (3′,5′,6-trimethyl- [1,1′-biphenyl]-3-yl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 559.9 (M + H)⁺;LCMS RT = 1.29 min. ++ Example 97 496

2-(3-(3′-cyano-4′,6- dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)570.9 (M + H)⁺; LCMS RT = 1.16 min. ++ Example 98 497

2-(3-(3′-fluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 549.6 (M + H)⁺;LCMS RT = 1.18 min. ++ Example 99 498

2-(3-(4′-fluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 549.6 (M + H)⁺;LCMS RT = 1.16 min. ++ Example 100 499

2-(5-cyclopropyl-3-(4- methyl-3-(pyridin-3- yl)phenyl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid; ¹H-NMR (MeOD) δ8.86 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.27(s, 1H), 8.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.64(dd, J = 8.0, 1.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 (s, 2H), 7.27(s, 1H), 4.25 (s, 2H), 2.42- 2.34 (m, 1H), 2.33 (s, 3H), 1.10 (dt, J =8.4, 4.6 Hz, 2H), 0.69 (dt, J = 5.6, 4.6 Hz, 2H); MS (ES) 572.9 (M +H)⁺; LCMS RT = 0.87 min. +++ Example 116 500

2-(3-(3′-amino-6- methyl-[1,1′-biphenyl]-3- yl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4- carboxylic acid; ; ¹H- NMR(MeOD) δ 8.26 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 8.0 Hz,1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.29 (s,1H), 7.27 (s, 3H), 7.18 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.23 (s, 2H),2.41- 2.33 (m, 1H), 2.27 (s, 3H), 1.08 (dt, J = 8.4,6.4 Hz, 2H), 0.67(dt, J = 5.6, 4.6 Hz, 2H); MS (ES) 586.9 (M + H)⁺; LCMS RT = 0.92 min.+++ Example 117 501

2-(3-(3-(benzyloxy) phenyl)-5-cyclopropyl-4- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H-NMR (MeOD) δ 8.24 (s, 1H),7.81 (d, J = 8.4 Hz, 2H), 7.40-7.34 (m, 4H), 7.31- 7.22 (m, 4H),7.14-7.09 (m, 2H), 6.99 (dd, J = 8.0, 2.0 Hz, 1H), 4.96 (s, 2H), 4.16(s, 2H), 2.37- 2.28 (m, 1H), 1.04 (dt, J = 8.4, 6.4 Hz, 2H), 0.63 (dt, J= 5.6, 4.8 Hz, 2H); MS (ES) 586.9 (M + H)⁺; LCMS RT = 0.92 min. +++Example 118 502

2-(5-cyclopropyl-3- (3-phenoxyphenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.24 (s,1H), 7.76 (d, J = 8.4 Hz, 2H), 7.40-7.31 (m, 4H), 7.19 (d, J = 8.4 Hz,2H), 7.13 (t, J = 8.4 Hz, 1H), 7.07 (s, 1H), 7.00 (dd, J = 8.0, 1.6 Hz,1H), 6.93 (d, J = 8.0 Hz, 2H), 4.15 (s, 2H), 2.37-2.29 (m, 1H), 1.03(dt, J = 8.4, 6.4 Hz, 2H), 0.62 (dt, J = 5.6, 4.8 Hz, 2H); MS (ES) 573.6(M + H)⁺; LCMS RT = 0.94 min. +++ Example 119 503

2-(5-(cyclopropylmethyl)- 3-(3-phenoxyphenyl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.19 (s,1H), 7.75 (d, J = 8.4 Hz, 2H), 7.38-7.31 (m, 4H), 7.20 (d, J = 8.4 Hz,2H), 7.15-7.10 (m, 2H), 7.02- 6.97 (m, 1H), 7.00 (dd, J = 8.0, 1.2 Hz,2H), 4.10 (s, 2H), 3.22 (d, J = 6.8 Hz, 2H), 1.12-1.06 (m, 1H),0.39-0.33 (m, 2H), 0.21 (dt, J = 6.0, 5.2 Hz, 2H); MS (ES) 587.7 (M +H)⁺; LCMS RT= 1.00 min. +++ Example 129 504

2-(5- (cyclopropylmethyl)- 3-(3- isopropoxyphenyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS(ES) 552.6 (M + H)⁺; LCMS RT = 0.98 min. +++ Example 130 505

2-(5- (cyclopropylmethyl)- 3-(3′-fluoro-5- methyl-[1,1′-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid; MS (ES) 603.7 (M + H)⁺; LCMS RT = 1.26 min. +++ Example141 506

2-(5- (cyclopropylmethyl)- 3-(4′-fluoro-5- methyl-[1,1′-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid; MS (ES) 603.4 (M + H)⁺; LCMS RT = 1.26 min. +++ Example142 507

2-(5-(cyclopropyl- methyl)-3-(3-(4- fluorophenoxy)phenyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H-NMR (MeOD) δ (ppm) 8.14 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.40 (t, J =8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.10- 7.04 (m, 2H), 7.01- 6.96(m, 4H), 6.84 (t, J = 2.0 Hz, 1H), 3.92 (s, 2H), 2.46 (d, J = 7.2 Hz,2H), 1.00- 0.90 (m, 1H), 0.44 (ddd, J = 8.4, 6.0, 4.4 Hz, 2H), 0.13 (dd,J = 10.0, 4.4 Hz, 2H); MS (ES) 605.2 (M + H)⁺; LCMS RT = 1.20 min. +++Example 134 508

2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR(d6-DMSO) δ 7.63 (d, J = 8.4 Hz, 2H), 7.42-7.33 (m, 4H), 7.23 (s, 2H),7.25 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 7.6 Hz,2H), 4.06 (s, 2H), 3.12 (d, J = 6.8 Hz, 2H), 0.87-0.80 (m, 1H), 0.30(ddd, J = 10.0, 6.0, 4.4 Hz, 2H), 0.13 (dd, J = 10.0, 5.2 Hz, 2H); MS(ES) 605.2 (M + H)⁺; LCMS RT = 1.18 min. +++ Example 135 509

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(3-fluoro- phenoxy)phenyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid;; ¹H-NMR (MeOD) δ 8.20 (s, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.50-7.46 (m,1H), 7.37-7.25 (m, 3H), 6.99 (s, 1H), 6.98 (d, J = 16.8 Hz, 1H), 6.88(dt, J = 8.4, 2.0 Hz, 1H), 6.73 (dt, J = 10.0, 2.0 Hz, 1H), 6.66 (dd, J= 8.4, 2.4 Hz, 1H), 4.13 (s, 2H), 3.24 (d, J = 6.8 Hz, 2H), 1.13-1.05(m, 1H), 0.44 (ddd, J = 8.0, 5.6, 4.0 Hz, 2H), 0.22 (dd, J = 10.4, 5.2Hz, 2H); MS (ES) 640.9 (M + H)⁺; LCMS RT = 1.19 min. +++ Example 136 510

2-(5-(cyclopropyl- methyl)-3-(4-fluoro- 3-(p-tolyloxy)phenyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylicacid; ¹H-NMR (MeOD) δ 8.19 (s, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.44-7.40(m, 1H), 7.25 (dd, J = 10.8, 8.8 Hz, 1H), 7.17-7.12 (m, 3H), 6.93 (s,1H), 6.92 (d, J = 17.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 4.07 (s, 2H),3.22 (d, J = 6.8 Hz, 2H), 1.11-1.04 (m, 1H), 0.37 (ddd, J = 8.0, 6.0,4.8 Hz, 2H), 0.21 (dd, J = 10.4, 5.2 Hz, 2H); MS (ES) 636.9 (M + H)⁺;LCMS RT = 1.12 min. +++ Example 137 511

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(4-fluoro- phenoxy)phenyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylicacid; ¹H-NMR (MeOD): δ 8.19 (s, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.45-7.41 (m, 1H), 7.26 (dd, J = 8.8, 11.0 Hz, 1H), 7.15 (dd, J = 2.2, 7.9Hz, 1H), 7.09 (dd, J = 8.5, 9.0 Hz, 2H), 6.98- 6.89 (m, 4H), 4.09 (s,2H), 3.23 (d, J = 7.05 Hz, 2H), 1.13-1.04 (m, 1H), 0.40-0.35 (m, 2H),0.23- 0.19 (m, 2H); MS (ES) 641.0 (M + H)⁺; LCMS RT = 1.18 min. +++Example 138 512

2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- (4-(trifluoromethyl)phenoxy)phenyl)-4-(3- fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H-NMR (MeOD) δ 8.28 (s, 1H), 7.73-7.67(m, 3H), 7.52-7.48 (m, 1H), 7.38 (dd, J = 2.1, 7.6 Hz, 1H), 7.30 (dd, J= 8.5, 10.5 Hz, 1H), 7.03-6.96 (m, 4H), 4.16 (s, 2H), 3.27 (d, J = 6.8Hz, 2H), 1.18-1.08 (m, 1H), 0.42-0.38 (m, 2H), 0.26-0.23 (m, 2H); MS(ES) 691.0 (M + H)⁺; LCMS RT = 1.24 min. +++ Example 139 513

2-(3-(3′-ethyl-6- fluoro-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (MeOD) δ 8.37 (s,1H), 8.17 (s, 1H), 7.86 (d, J = 8.24 Hz, 2H), 7.77 (d, J = 6.4 Hz, 2H),7.44 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 9.62 Hz, 1H), 7.16 (d, J = 7.79Hz, 2H), 7.03 (m, 1H), 4.23 (s, 2H), 3.63 (q, J = 7.1, 14.2 Hz, 2H),1.20 (t, J = 7.1 Hz, 3H); MS (ES) 562.9 (M + H)⁺; LCMS RT = 1.24 min. ++Example 101 514

2-(3-(3′,5′-dichloro-6- fluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR(MeOD) δ 8.36 (s, 1H), 8.16 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.81 (m,2H), 7.75 (d, J = 8.1 Hz, 2H), 7.46 (M, 2H), 7.34 (m, 2H), 4.24 (s, 2H);MS (ES) 602.9 (M + H)⁺; LCMS RT = 1.30 min. + Example 102 515

2-(3-(6-fluoro- [1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 544.0 (M + H)⁺;LCMS RT = 1.18 min. +++ Example 103 516

2-(3-(6-fluoro-3′,4′- dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)562.9 (M + H)⁺; LCMS RT = 1.23 min. ++ Example 104 517

2-(4-(4- sulfamoylbenzyl)-3- (3′,4′,6-trifluoro-[1,1′-biphenyl]-3-yl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)571.0 (M + H)⁺; LCMS RT = 1.18 min. ++ Example 105 518

2-(3-(4′,6-difluoro-3′- methoxy-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)582.9 (M + H)⁺; LCMS RT = 1.14 min. +++ Example 106 519

2-(3-(3′-methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 530.9 (M + H)⁺;LCMS RT = 1.00 min. +++ Example 107 520

2-(3-(3′,6-difluoro-4′- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)566.9 (M + H)⁺; LCMS RT = 1.22 min. ++ Example 108 521

2-(3-(3′-methoxy- [1,1′-biphenyl]-3-yl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 546.9 (M + H)⁺;LCMS RT = 0.89 min. +++ Example 109 522

2-(3-(3-(pyridin-3- yl)phenyl)-4-(4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid; MS (ES) 517.9 (M + H)⁺; LCMS RT = 0.82min. ++ Example 110 523

2-(5- (cyclopropylmethyl)- 3-(3′,5-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES)607.0 (M + H)⁺; LCMS RT = 1.10 min. ++ 524

2-(3-(3′-amino-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 532.0 (M + H)⁺;LCMS RT = 0.70 min. ++ Example 111 525

4-((3-(cyclopropyl- methyl)-5-(3′,5-difluoro- [1,1′-biphenyl]-3-yl)-1-(4-((oxo-13-methyl)- 13-oxidanyl)thiazol-2- yl)-1H-pyrazol-4-yl)methyl)benzene- sulfonamide; ¹H-NMR (CDCl₃) δ 7.96 (s, 1H), 7.84 (d,J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.24 (m, 4H) 7.06 (m, 4H), 3.93 (s, 2H)2.53 (d, J = 6.8 Hz, 2H), 1.05 (m, 1H), 0.55 (m, 2H), 0.22 (d, J = 5.8Hz, 2H); MS (ES) 607.0 (M + H)⁺; LCMS RT = 0.95 min. + Example 133 526

2-(5-(cyclopropylmethyl)- 3-(3-(3-fluorophenoxy) phenyl)-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid; ¹H-NMR (MeOD) δ7.89 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.42 (m, 2H), 7.34 (m, 2H), 7.23(d, J = 8.4 Hz, 2H), 7.12 (m, 1H) 8.87 (m, 2H), 6.70 (m, 2H), 4.13 (s,2H), 3.25 (d, J = 6.7 Hz, 2H), 0.32 (d, J = 8.2 Hz, 2H), 0.12 (d, J =4.39 Hz, 2H); MS (ES) 605.2 (M + H)⁺; LCMS RT = 1.21 min. ++ Example 140527

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-((4-fluoro-benzyl)oxy)phenyl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (MeOD) δ 8.21 (s, 1H), 7.83 (d, J = 8.4 Hz,2H), 7.40 (m, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.23 (m, 1H), 7.17 (m, 1H),7.107 (m, 3H), 4.96 (s, 2H), 4.13 (s, 2H), 3.25 (d, J = 6.83 Hz, 2H),1.12 (m, 1H), 0.38 (d, J = 8.1 Hz, 2H), 0.23 (d, J = 5.1 Hz, 2H); MS(ES) 636.9 (M + H)⁺; LCMS RT = 1.12 min. +++ Example 131 528

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-((3-fluoro-benzyl)oxy)phenyl)-4- (3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR (MeOD) δ 8.19 (s, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.40 (m, 1H), 7.23 (m, 3H), 7.16 (m, 2H), 7.04 (m, 3H),5.08 (s, 2H), 4.11 (s, 2H), 3.25 (d, J = 6.5 Hz), 1.11 (m, 1H), 0.39 (d,J = 7.8 Hz), 0.23 (d, J = 4.6 Hz); MS (ES) 655.0 (M + H)⁺; LCMS RT =1.19 min. +++ Example 132 529

2-(3-(3,4-difluorophenyl)- 1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s,1H), 8.24 (s, 1H), 7.70-7.59 (m, 2H), 7.57 (s, 2H), 7.49 (dd, J = 7.2,2.3 Hz, 1H), 7.37 (dd, J = 10.0, 8.6 Hz, 1H), 7.10 (dd, J= 11.3, 1.6 Hz,1H), 7.01 (dd, J = 8.1, 1.6 Hz, 1H), 6.30 (dt, J = 2.1, 1.0 Hz, 1H),5.95 (s, 1H), 4.12 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.18-0.99 (m, 0H),0.38-0.27 (m, 2H), 0.25-0.15 (m, 2H); MS (M + H)+ = 625 +++ Example 145530

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(2-methyl-prop-1-en-1-yl)phenyl)- 4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s,1H), 8.26 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.56 (s, 2H), 7.45 (ddd, J= 8.4, 5.0, 2.3 Hz, 1H), 7.34 (dd, J = 7.5, 2.2 Hz, 1H), 7.21 (dd, J =10.0, 8.5 Hz, 1H), 7.14-6.99 (m, 2H), 6.23-6.09 (m, 1H), 4.11 (s, 2H),3.13 (d, J = 6.9 Hz, 2H), 1.85 (d, J = 1.4 Hz, 3H), 1.54 (t, J = 1.1 Hz,3H), 1.18-1.04 (m, 1H), 0.36-0.27 (m, 2H), 2H); MS (M + H)+ = 585 +++145 531

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(prop-1-en-2-yl)phenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.17 (s, 1H), 8.28 (s, 1H), 7.73-7.61 (m, 2H), 7.61- 7.49 (m, 3H), 7.37(dd, J = 11.3, 8.6 Hz, 1H), 7.17 (dd, J = 11.3, 1.6 Hz, 1H), 7.07 (s,1H), 7.10-7.02 (m, 1H), 6.79 (ddd, J = 4.2, 2.2, 1.1 Hz, 1H), 4.16 (s,2H), 3.16 (d, J = 7.0 Hz, 2H), 1.24- 1.06 (m, 1H), 0.38-0.28 (m, 2H),0.32-0.17 (m, 2H); MS (M + H)+ = 632 +++ 145 532

(E)-2-(5-(cyclopropyl- methyl)-3-(3-(2-cyclo- propylvinyl)-4-fluoro-phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s,1H), 7.64 (t, J = 7.9 Hz, 1H), 7.57 (s, 2H), 7.51 (dd, J = 7.4, 2.3 Hz,1H), 7.42 (ddd, J = 8.6, 5.0, 2.2 Hz, 1H), 7.23-7.10 (m, 2H), 7.03 (dd,J = 8.1, 1.6 Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 5.64 (dd, J = 15.9, 9.4Hz, 1H), 4.13 (s, 2H), 3.14 (d, J = 6.7 Hz, 2H), 1.59 (dddd, J = 12.8,9.4, 8.1, 4.7 Hz, 1H), 1.24- 0.96 (m, 1H), 0.84-0.74 (m, 2H), 0.55-0.46(m, 2H), 0.37-0.16 (m, 4H); MS (M + H)+ = 597 +++ 145 533

(E)-2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- (prop-1-en-1-yl)phenyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylicacid, 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.65 (t,J = 7.9 Hz, 1H), 7.60- 7.49 (m ,3H), 7.43 (ddd, J = 8.5, 5.0, 2.3 Hz,1H), 7.24-7.11 (m, 2H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.45 (dq, J =15.8, 1.6 Hz, 1H), 6.11 (dq, J = 16.0, 6.6 Hz, 1H), 4.12 (s, 2H), 3.16(d, J = 7.0 Hz, 2H), 1.83 (dd, J = 6.6, 1.7 Hz, 3H), 1.20-1.06 (m, 1H),0.38- 0.28 (m, 2H), 0.25-0.17 (m, 2H); MS (M + H)+ = 571 +++ 145 534

2-(5-(cyclopropyl- methyl)-3-(4-fluoro-3- (prop-1-en-2-yl)phenyl)-4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylicacid, 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t,J = 7.9 Hz, 1H), 7.57 (s, 2H), 7.50 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H),7.40 (dd, J = 7.5, 2.3 Hz, 1H), 7.23 (dd, J = 11.1, 8.5 Hz, 1H), 7.13(dd, J = 11.4, 1.6 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 5.24 (dp, J= 2.4, 1.2 Hz, 1H), 5.14 (dq, J = 1.8, 0.9 Hz, 1H), 4.12 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 1.96 (q, J = 1.0 Hz, 3H), 1.24-0.93 (m, +++ 1451H), 0.37-0.28 (m, 2H), 0.25-0.16 (m, 2H); MS (M + H)+ = 571 535

(E)-2-(3-(3-(2-cyclo- pentylvinyl)-4-fluoro- phenyl)-5-(cyclopropyl-methyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s,1H), 7.65 (t, J = 7.9 Hz, 1H), 7.59-7.43 (m, 4H), 7.25- 7.12 (m, 2H),7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.41 (dd, J = 16.0, 1.1 Hz, 1H), 6.08(dd, J = 16.0, 8.0 Hz, 1H), 4.14 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),2.63- 2.49 (m, 1H), 1.83-1.62 (m, 2H), 1.66-1.48 (m, 2H), 1.31 (s, 1H),1.39- 1.24 (m, 1H), 1.20-1.05 (m, 1H), 0.37-0.28 (m, 2H), 0.29-0.16 (m,2H); MS (M + H)+ = 625 +++ 145 536

ethyl 2-(3-(3-(cyclo- pentylethynyl)-4-fluoro- phenyl)-5-(cyclopropyl-methyl)-4-(3-sulfamoyl- benzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylate,1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.61 (dt, J = 7.9, 1.4 Hz,1H), 7.53 (s, 1H), 7.56- 7.49 (m, 1H), 7.53-7.38 (m, 2H), 7.36-7.21 (m,2H), 7.28 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.14 (d, J =6.9 Hz, 2H), 2.87 (p, J = 7.3 Hz, 1H), 2.01-1.89 (m, 1H), 1.94 (s, 1H),1.72-1.50 (m, 7H), − 145 1.30 (t, J = 7.1 Hz, 3H), 1.12 (s, 1H),0.37-0.17 (m, 4H); MS (M + H )+ = 633 537

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((1- methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, MS (M + H)+ = 635 145 538

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(4-methyl-pent-1-yn-1-yl)phenyl)- 4-(3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s,1H), 8.28 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.59- 7.49 (m, 4H), 7.29(ddd, J = 9.2, 8.0, 1.1 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02(dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.14 (d, J = 6.8 Hz, 3H), 2.34(d, J = 6.4 Hz, 2H), 1.83 (dp, J = 13.2, 6.6 Hz, 1H), 1.11 (dddd, J =14.9, 8.0, 4.9, 1.9 Hz, 1H), 0.97 (d, J = +++ 145 6.7 Hz, 6H), 0.37-0.25(m, 2H), 0.26-0.15 (m, 2H); MS (M + H)+ = 611 539

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(pent-1-yn-1-yl)phenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.16 (s, 1H), 8.28 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.57 (s, 2H),7.58-7.49 (m, 2H), 7.33-7.24 (m, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H),7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.17-3.11 (m, 3H), 2.42(t, J = 6.9 Hz, 2H), 1.54 (q, J = 7.1 Hz, 2H), 1.18-1.03 (m, 1H), 0.97(t, J = 7.4 Hz, 3H), 0.37-0.27 (m, 2H), 0.24- +++ 145 0.15 (m, 2H); MS(M + H)+ = 597 540

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(hex-l -yn-1-yl)phenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4- carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.16 (s, 1H), 8.28 (s, 1H), 7.57 (s, 2H), 7.69-7.48 (m, 3H), 7.28 (dd,J = 9.4, 8.6 Hz, 1H), 7.13 (dd, J = 11.4, 1.6 Hz, 1H),7 .02 (dd, J =8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.18-3.11 (m, 3H), 2.44 (t, J = 6.9 Hz,2H), 1.57-1.34 (m, 4H), 1.18- 1.03 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H),0.37-0.27 (m, +++ 145 2H), 0.24-0.16 (m, 2H); MS (M + H)+ = 611 541

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((5- methylfuran-2-yl)ethynyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, MS (M + H)+ = 635 145 542

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (trifluoromethyl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylicacid (M + H)+ = 599 +++ 49 543

2-(3-(3-(tert-butyl- carbamoyl)-4-fluoro- phenyl)-5-(cyclopropyl-methyl)-4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid: ¹H-NMR(MeOD) δ: 8.21 (s, 1H), 7.79-7.69 (m,3H), 7.19 (dd, J = 8.6, 10.0 Hz, 1H), 7.11- 7.05 (m, 2H), 4.21 (s, 2H),3.28 (d, J = 6.8 Hz, 2H), 1.44 (s, 9H), 1.18- 1.10 (m, 1H), 0.43-0.39(m, 2H), 0.28-0.24 (m, 2H); MS (ES) 630.1 (M + H)⁺, LCMS RT = 1.048 min.+++ 162 544

2-(3-(3- (benzylcarbamoyl)-4- fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylicacid: MS (ES) 664.0 (M + H)⁺, LCMS RT = 1.052 min. +++ 162 545

2-(5-(cyclopropylmethyl)- 3-(4-fluoro-3-(pyrrolidine-1-carbonyl)phenyl)-4- (3-fluoro-4-sulfamoyl- benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid: ¹H-NMR (MeOD) δ: 8.22 (s, 1H), 7.75-7.71(m, 2H), 7.54 (dd, J = 2.2, 6.4 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.07(t, J = 7.4 Hz, 2H), 4.20 (s, 2H), 3.59 (t, J = 7.1 Hz, 2H), 3.30 (d, J= 6.9 Hz, 2H), 3.19 (t, J = 2H), 2.03-1.91 (m, 4H), 0.95-0.86 (m, 1H),0.45-0.40 (m, 2H), 0.29- 0.25 (m, 2H); MS (ES) 628.0 (M + H)⁺, LCMS RT =0.968 min. +++ 163 546

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (morpholine-4-carbonyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid: MS (ES) 644.0 [M + H]⁺, LCMS RT = 0.977min. 163

Example 165

This example describes the inhibition of lactate production, as measuredby the assay set forth in Example 1, of exemplary compounds of formula(I) in an embodiment of the invention. See Table 8. The lactate activityin Table 8 is represented by 0 to 3 pluses as follows: +++<1 μM; ++1-10μM; +10-57 μM; and −>57 RM.

TABLE 8 Cmpd Lactate ID activity 42 ++ 43 + 47 − 52 ++ 53 − 54 − 160 ++183 +++ 189 ++ 203 +++ 206 ++ 207 ++ 212 − 213 − 214 ++ 215 + 217 ++ 219++ 221 +++ 223 +++ 227 +++ 229 − 230 +++ 231 +++ 232 +++ 233 +++ 234 +++237 ++ 239 +++ 251 ++ 252 ++ 257 +++ 258 +++ 259 + 260 ++ 261 ++ 262 +++263 + 264 +++ 265 ++ 266 − 267 + 268 − 269 +++ 276 +++ 281 +++ 284 +++288 +++ 290 +++ 294 +++ 296 ++ 304 + 306 +++ 307 +++ 309 +++ 310 +++ 324+++ 326 +++ 327 + 330 +++ 331 +++ 332 +++ 336 +++ 337 +++ 338 +++ 364+++ 365 +++ 366 +++ 367 +++ 368 + 369 + 370 ++ 371 +++ 372 ++ 373 +++374 +++ 375 ++ 376 +++ 377 − 378 +++ 379 +++ 380 ++ 381 +++ 382 +++ 383+++ 384 +++ 385 +++ 386 +++ 387 ++ 388 ++ 389 ++ 390 − 391 +++ 393 −394 + 395 + 396 ++ 397 ++ 398 + 399 − 400 +++ 401 +++ 402 +++ 403 +++404 +++ 405 +++ 406 ++ 407 +++ 408 +++ 409 ++ 410 +++ 411 +++ 412 ++ 413+++ 414 ++ 415 ++ 416 ++ 417 ++ 418 ++ 419 +++ 420 − 421 ++ 422 + 423+++ 428 − 429 − 430 +++ 431 +++ 432 +++ 433 +++ 434 − 435 − 436 +++ 437+++ 438 ++ 439 − 440 ++ 442 ++ 443 +++ 444 +++ 445 +++ 446 +++ 458 ++467 +++ 468 ++ 469 ++ 470 ++ 471 ++ 472 +++ 473 +++ 477 +++ 478 ++ 479+++ 480 +++ 481 ++ 485 ++ 501 ++ 502 ++ 503 ++ 504 ++ 505 ++ 506 ++ 507++ 508 ++ 509 +++ 510 +++ 511 ++ 512 +++ 523 ++ 526 + 527 ++ 528 +++ 542++ 543 ++ 544 ++ 545 +

Example 167

This example evaluates the pharmacokinetics (PK) of compound 42 whenadministered orally as the ethyl ester prodrug (compound 141) to in anembodiment of the invention.

Compound 141 is the ethyl ester prodrug of compound 42. A doseformulation was freshly prepared comprising either compound 42 orcompound 141, in a solution of 10% N-methyl-2-pyrrolidone (NMP), 40%PEG400, and 50% of SOLUTOL™ (30%) in water to provide a concentration of1 mg/mL of compound 42 or 141. The dose formulation was stirred at roomtemperature and used within 30 minutes after preparing.

Male CD1 mice obtained from Si Bei Fu Laboratory Animal Technology Co.Ltd were fed prior to dosing. On the first day of dosing, the miceranged in age from about 7-9 weeks and weighed approximately 20-30 g.The mice were orally administered 10 mL/kg (10 mg/kg) of the formulationcomprising either compound 42 or 141.

PK measurements were taken at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h,12, h, and 24 h post dose. For sample collections, approximately 0.03 mLblood was collected by the dorsal metatarsal vein at each time point.All blood samples were transferred into plastic micro centrifuge tubescontaining 2 microliters (μL) of 1,000 IU heparin as anti-coagulant.Collection tubes with blood samples and anticoagulant were invertedseveral times for proper mixing of the tube contents and then placed onwet ice prior to centrifugation for plasma. Blood samples werecentrifuged at 4,000 g for 5 minutes at 4° C. to obtain plasma. Plasmasamples were stored in polypropylene tubes, quickly frozen in an icebox, and kept at −75±15° C. Plasma samples were analyzed using anLC/MS/MS method. The peak concentration (C_(max)), area under the curve(AUC_(last)), and the fraction of the dose that enters systemiccirculation (F) of compounds 42 and 142 are set forth below in Table 9.

TABLE 9 C_(max) AUC_(last) F Compound (ng/mL) (h · ng/mL) (%) 42 1591214 34 141 851 2409 69

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The invention claimed is:
 1. A compound of formula (Ia):

wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each independently CH or N; R¹ isindependently chosen from halo, —C(O)R⁴, —CH₂OH, —C(O)NHCN, —C(O)NHSO₂H,—C(S)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —(C₁-C₈hydrocarbyl), —C(O)NHOH,—C(O)OCR⁵R⁶OC(O)OR⁴, —P(O)(OH)₂, —B(OR¹³)(OR¹⁴), —SO₂(OH),—C(O)NHS(O)₂Me, —SO₂NR⁵R⁶—(C₀-C₄hydrocarbyl)(mono- or bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), and —C(O)O—(C₀-C₄hydrocarbyl)(mono- or bicyclic heterocyclehaving 1 to 4 heteroatoms independently chosen from N, O, and S), eachof which R¹ except halo, —P(O)(OH)₂, and —SO₂(OH), is substituted orunsubstituted; R² is independently chosen from hydroxyl, halo, —CN,—NO₂, C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; R³ is independently chosen from hydroxyl, halo, —CN,—NO₂, —SF₅, C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or two R³ moieties and the phenyl group to which they areattached form a naphthyl group or its heterocyclic analog that isoptionally substituted; each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same ordifferent and each is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆cycloalkyl, C₆-C₁₂aryl, C₁-C₁₂heteroaryl, or C₁-C₁₂heterocycloalkyl,each of which C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂aryl,C₁-C₁₂heteroaryl, or C₁-C₁₂heterocycloalkyl is substituted orunsubstituted; R¹⁰ is hydrogen, halo, —CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵(SO₂)R⁴, —NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶, —NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴,C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁰except hydrogen, halo, —CN, and —NO₂ is substituted or unsubstituted;each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring; X¹ is a bond,—CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O)—, —O—, —CO—, —SO—, —SO₂—,or —S—; X² is —NR⁵—, —O—, —SO₂—, or —S—; m, n, and q are the same ordifferent and each is 0, 1, 2, 3, 4, or 5; and p is 1 or 2, or a prodrugor pharmaceutically acceptable salt thereof.
 2. The compound or salt ofclaim 1, wherein R¹ is independently chosen from hydroxyl, halo, —CO₂H,—SO₂NH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl optionally substitutedwith halo, C₁-C₂haloalkoxy, and —CO₂(C₁-C₆ alkyl), R² is chosen from Fand —SO₂NH₂, where one of R² is —SO₂NH₂; R³ is independently chosen from(a) halogen, hydroxyl, SF₅; (b) C₁-C₆hydrocarbyl where any alkylene(CH₂) group in the hydrocarbyl chain is optionally replaced with NH, O,or S; (c) —C₀-C₂hydrocarbyl (phenyl), —C₀-C₂hydrocarbyl (phenyl),—C₀-C₂hydrocarbyl (thiophenyl), —C₀-C₂hydrocarbyl (oxazolyl),—C₀-C₂hydrocarbyl(thiazolyl), —C₀-C₂hydrocarbyl (tetrahydrofuranyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkyl), —C₀-C₂hydrocarbyl(C₃-C₆cycloalkyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkanyl),—C₀-C₂hydrocarbyl(C₃-C₆cycloalkenyl), —C₀-C₂hydrocarbyl(tetrahydropyrenyl), —C₀-C₂hydrocarbyl (imidazolyl),—C₀-C₂hydrocarbyl(thiophenyl), where any alkylene (CH₂) group in theC₀-C₂hydrocarbyl chain is optionally replaced with NH, O, or S; whereeach of (b) is unsubstituted or substituted with 1 or more substituentsindependently chosen from halogen, hydroxyl, cyano, amino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; where each of (c) is unsubstitutedor substituted with 1 or more substituents independently chosen fromhalogen, hydroxyl, cyano, amino, C₁-C₄alkyl, C₁-C₆cycloalkyl, mono- ordi-C₁-C₄alkylamino, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy. 3.The compound or salt of claim 2, wherein one of R² is —SO₂NR⁵R⁶ and R⁵and R⁶ are the same or different and each is H or C₁-C₈ alkyl and nis
 1. 4. The compound or salt of claim 2, wherein each R³ isindependently halo, C₁-C₈ haloalkyl, C₃-C₈ haloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, or substitutedor unsubstituted phenyl, and m is 1 or
 2. 5. The compound or salt ofclaim 4, wherein X¹ is —CH₂— and X² is —S.
 6. The compound or salt ofclaim 1, wherein only one of Y¹, Y², Y³, Y⁴, and Y⁵ is N.
 7. Thecompound or salt of claim 1, wherein the compound is a compound offormula (Ia-1)

wherein R^(a) is —R⁴, —OR⁴, or NR⁵R⁶, each of which is substituted orunsubstituted; R^(b) and R^(c) are the same or different and each is Hor substituted or unsubstituted C₁-C₈ alkyl; R² is independently chosenfrom hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₁-C₈alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)—SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, and—(CH₂)_(q)heterocycloalkyl, each of which R² except hydroxyl and halo issubstituted or unsubstituted; R³ is independently chosen from hydroxyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,—(C₁-C₄hydrocarbyl)C₃-C₆cycloalkyl, C₁-C₈ alkoxy,—(C₀-C₄alkoxy)C₃-C₆cycloalkyl, —(C₀-C₄alkoxy)aryl, halo, C₁-C₈haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴,—CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(C₀-C₄hydrocarbyl)aryl,—(C₀-C₄hydrocarbyl)heteroaryl, —(C₀-C₄alkoxy)heteroaryl,—(C₀-C₄alkoxy)heterocycloalkyl, and —(C₀-C₄hydrocarbyl)heterocycloalkyl, each of which R³ except hydroxyl and halo issubstituted or unsubstituted; or two R³ moieties and the phenyl group towhich they are attached form a naphthyl group that is optionallysubstituted; each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same or differentand each is hydrogen, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of whichC₁-C₈ alkyl and C₃-C₆ cycloalkyl is substituted or unsubstituted; R¹⁰ ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy, halo, C₁-C₈haloalkyl, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, or—SO₂R⁴, each of which R¹⁰ except hydrogen, hydroxyl and halo issubstituted or unsubstituted; X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —O—, —S(O)—,or —S(O)₂—, or —S—, each of which R⁸ and R⁹ is substituted orunsubstituted; n is an integer from 0 to 4; and m and q are the same ordifferent and each is 0 or an integer from 1-5, or a prodrug, orpharmaceutically acceptable salt thereof.
 8. The compound or salt ofclaim 7, where R^(a) is R⁴, —OR⁴, or —NR⁵R⁶; R² is one or moresubstituents independently chosen from halo, hydroxyl, —CN, —NO₂, amino,—C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, C₁-C₂ alkyl, C₁-C₂ alkoxy,C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; each R⁴, R⁵, and R⁶, is the sameor different and each is hydrogen or C₁-C₂ alkyl; and R¹⁰ is hydrogen,hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl, C₁-C₄ alkoxy,C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴; and one of R³ is selectedfrom C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is chosen from thienyl, furanyl, thiazolyl, pyrazolyl,imidazolyl; each of which one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy; and 0 or 1 or more R³ is selected from hydroxyl, halo,—CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy. 9.The compound or salt of claim 7, wherein the compound is a compound offormula (Ia-2):

wherein Y=—CH═CH—, O, S, NH; R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each ofwhich R⁴-R⁵, and R⁶ is substituted or unsubstituted; each R² is the sameor different and is hydrogen, hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, C₁-C₈ alkoxy, C₃-C₆cycloalkyloxy, aryloxy, halo, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl,haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, (CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which R² except hydrogen, hydroxyland halo is substituted or unsubstituted; each R¹¹ and R¹² isindependently selected from hydroxyl, halo, —CN, NO₂, C₁-C₈ alkyl, C₂-C₈alkenylC₁-C₈ alkoxy, C₁-C₂ haloalkoxy, C₁-C₂ haloalkyl, C(O)R⁴, CO₂R⁴,C(O)NR⁵R⁶, NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, and—(CH₂)_(q)SO₂R⁴, each of which R¹¹ and R¹² other than hydroxyl, halo,—CN, and NO₂, is substituted or unsubstituted; each R⁴, R⁵, R⁶, and R⁷is the same or different and each is hydrogen, C₁-C₈ alkyl, or C₃-C₆cycloalkyl, each of which C₁-C₈ alkyl and C₃-C₆ cycloalkyl issubstituted or unsubstituted; R¹⁰ is hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl,hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy, halo, C₁-C₈ haloalkyl, aryl,arylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴, each of which R¹⁰ excepthydrogen and halo is substituted or unsubstituted; m and q are the sameor different and each is 0 or 1, 2, 3, 4, or 5; and m′ is 0 or aninteger from 1-4.
 10. The compound or salt of claim 7, wherein thecompound is a compound of formula (Ia-3):

wherein R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R⁴, R⁵, and R⁶ issubstituted or unsubstituted; each R² is the same or different and eachis hydrogen, hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo,C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂,—C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R²except hydrogen, hydroxyl, and halo is substituted or unsubstituted; R³is hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴,—CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(ci)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R³except hydroxyl and halo is substituted or unsubstituted; R^(d) ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy, halo, C₃-C₈haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN, —CO₂R⁴,—NR⁵R⁶, or —SO₂R⁴, each of which R^(d) except halo and —CN issubstituted or unsubstituted; each R⁴, R⁵, R⁶, and R⁷ is the same ordifferent and each is hydrogen, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, eachof which C₁-C₈ alkyl and C₃-C₆ cycloalkyl are substituted orunsubstituted; q is 0 or and integer from 1-5; m′ is 0 or an integerfrom 1-4; and R¹⁰ is hydrogen, C₃-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylalkyl, hydroxyl,hydroxyalkyl, C₁-C₈ alkoxy, halo, C₁-C₈ haloalkyl, aryl, arylalkyl,heteroarylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴, each of which R¹⁰except hydrogen, hydroxy, and halo is substituted or unsubstituted. 11.The compound or salt of claim 10, wherein R^(a) is hydrogen, hydroxyl,amino, C₁-C₂alkyl, C₁-C₂alkoxy, and mono- or di-C₁-C₂alkylamino-; eachR² is the same or different and is independently selected from hydrogen,halo, hydroxyl, —CN, —NO₂, amino, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶,—NR⁵C(O)R⁴, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₃-C₂ haloalkyl, andC₁-C₂haloalkoxy; each R³ is independently chosen from hydroxyl, halo,—CN, NO₂, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkoxy, and C₁-C₂haloalkyl; each R⁴, R⁵, R⁶, and R⁷ is the same or different and each ishydrogen or C₁-C₂ alkyl; m′ is 0 or an integer from 1-4; and R¹⁰ ishydrogen, hydroxyl, halo, —CN, C₁-C₄ alkyl, hydroxylC₁-C₄alkyl, C₁-C₄alkoxy, C₂-C₄ alkenyl, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, —CO₂R⁴, —NR⁵R⁶, or —SO₂R; R^(d) is thienyl substitutedwith methyl.
 12. The compound or salt of claim 9, wherein R^(a) ishydroxyl or substituted or unsubstituted —O(C₁-C₈ alkyl); R² ishydrogen, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, or halo; R¹¹ and R¹² are each independentlyselected from substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₈ alkoxy, or halo; R¹⁰ is hydrogen, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted cyclopropyl,substituted or unsubstituted —CH₂-cyclopropyl, substituted orunsubstituted —CH═CH₂, substituted or unsubstituted —C≡C-cyclopropyl,substituted or unsubstituted phenyl, substituted or unsubstitutedbenzyl, —I, —CF₃, —NH₂, or —CN; m is 0, 1, or 2; and m′ is
 0. 13. Thecompound or salt of claim 7, wherein the compound is a compound offormula (Ia-4):

wherein R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R^(4′) R⁵, and R⁶is substituted or unsubstituted; each R² is the same or different and ishydrogen, hydroxyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, aryloxy, halo, C₁-C₈haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN, —NO₂, —C(O)R⁴,—CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R²except hydrogen, hydroxyl and halo is substituted or unsubstituted; R³is selected from C₂-C₆alkynyl, —(C₀-C₂alkyl)C₃-C₆cycloalkyl,—(C₂-C₄alkenyl)C₃-C₆cycloalkyl, —(C₂-C₄alkynyl)C₃-C₆cycloalkyl,—(C₀-C₂alkoxy)C₃-C₆cycloalkyl, dihydropyranyl, —(C₀-C₄alkoxy)phenyl,—(C₀-C₄alkyl)phenyl, —(C₂-C₄alkenyl)phenyl, —(C₂-C₄alkynyl)phenyl,—(C₀-C₄alkoxy)heteroaryl, —(C₀-C₄alkyl)heteroaryl,—(C₂-C₄alkenyl)heteroaryl, and —(C₂-C₄alkynyl)heteroaryl, whereheteroaryl is a 5- or 6-membered heteroaryl having 1, 2, 3, or 4heteroatoms independently chosen from N, O, and S, and where each R³ isunsubstituted or substituted with one or more substituents selected fromhydroxyl, halo, —CN, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄alkoxy, (C₃-C₆ cycloalkyl)C₀-C₂alkyl, C₁-C₂ haloalkyl, andC₁-C₂haloalkoxy; each R¹¹ is independently selected from hydroxyl, halo,—CN, NO₂, C₁-C₈ alkyl, C₂-C₈ alkenylC₁-C₈ alkoxy, C₁-C₂ haloalkoxy,C₁-C₂ haloalkyl, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴,—(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶,—(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶, and —(CH₂)_(q)SO₂R⁴, each of whichR¹¹ and R¹² other than hydroxyl, halo, —CN, NO₂, is substituted orunsubstituted; each R⁴, R⁵, R⁶, and R⁷ is the same or different and eachis hydrogen, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl, each of which C₁-C₈ alkyland C₃-C₆ cycloalkyl is substituted or unsubstituted; R¹⁰ is hydrogen,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy, halo, C₁-C₈haloalkyl, aryl, arylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶, or —SO₂R⁴, each ofwhich R¹⁰ except hydrogen and halo is substituted or unsubstituted; m is0 or 1, 2, 3, 4, or 5; and m′ is 0 or an integer from 1-4.
 14. Acompound or salt of formula (Ib):

wherein R¹ is independently chosen from halo, —CO₂R⁴, —C(O)NR⁵R⁶,—(C₁-C₈hydrocarbyl), —C(O)NHOH, —C(O)OCR⁵R⁶OC(O)OR⁴,—(C₀-C₄hydrocarbyl)((mono- or bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—C(O)O—(C₀-C₄hydrocarbyl)(mono- or bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —P(O)(OH)₂,—B(OR¹³)(OR¹⁴), —SO₂(OH), —C(O)NHS(O)₂Me and —SO₂NR⁵R⁶, each of which R¹except halo is substituted or unsubstituted; R² is independently chosenfrom hydroxyl, halo, —CN, —NO₂, C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or—(CH₂)_(q)heterocycloalkyl, each of which C₁-C₈hydrocarbyl,—O(C₁-C₈hydrocarbyl), —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—O(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S),—(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; R³ is independently chosen from hydroxyl, halo, —CN,—NO₂, —SF₅, C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), —C(O)R⁴, —CO₂R⁴,—C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴, —(CH₂)_(q)NR⁵C(O)R⁴,—(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶, —(CH₂)_(q)SO₂NR⁵R⁶,—(CH₂)_(q)SO₂R⁴, each of which C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S) is substituted orunsubstituted; or each R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ is the same ordifferent and each is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, each of which C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, orheterocycloalkyl is substituted or unsubstituted; R¹⁰ is hydrogen, halo,—CN, —NO₂, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵(SO₂)R⁴, —NR⁵C(O)R⁴, —NR⁷C(O)NR⁵R⁶,—NR⁵R⁶, —SO₂NR⁵R⁶, —SO₂R⁴, C₁-C₈hydrocarbyl, —O(C₁-C₈hydrocarbyl),—(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkyl, —O(C₀-C₄hydrocarbyl)C₃-C₈cycloalkyl, —(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl,—O(C₀-C₄hydrocarbyl)C₃-C₈ cycloalkenyl, —O(C₀-C₄hydrocarbyl)C₆-C₁₂aryl,—(C₀-C₄hydrocarbyl)C₆-C₁₂aryl, —O(C₀-C₄hydrocarbyl)(mono- and bicyclicheterocycle having 1 to 4 heteroatoms independently chosen from N, O,and S), —(C₀-C₄hydrocarbyl)(mono- and bicyclic heterocycle having 1 to 4heteroatoms independently chosen from N, O, and S), each of which R¹⁰except hydrogen, halo, —CN, and —NO₂ is substituted or unsubstituted;each R¹³ and R¹⁴ is the same or different and each is hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, C₆-C₁₂ aryl, wherein R¹³ and R¹⁴are optionally connected to each other to form a ring; X¹ is a bond,—CR⁸R⁹—, —NR⁵—, —CR⁸NR⁵—, —NR⁵CR⁸—, —NR⁵C(O)—, —O—, —CO—, —SO—, —SO₂—,or —S—; X² is —NR⁵—, —O—, or —SO₂—, or —S—; X³ is CH or N; m and o arethe same or different and each is 0 or an integer from 1-5; n is aninteger from 1-5; and p is 1 or
 2. 15. The compound or salt of claim 14,wherein R¹ is —CO₂H or —CO₂(C₁-C₈ alkyl), wherein the C₁-C₈ alkyl issubstituted or unsubstituted; R² is —SO₂NR⁵R⁶ and R⁵ and R⁶ are the sameor different and each is H or C₁-C₈ alkyl; n is 1; R³ is independentlyhalo, C₁-C₈ haloalkyl, C₁-C₈ haloalkoxy, substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted—(CH₂)_(q)aryl, substituted or unsubstituted —(CH₂)_(q)heteroaryl, orsubstituted or unsubstituted —(CH₂)_(q)heterocycloalkyl; m is 0, 1, or2; R¹⁰ is substituted or unsubstituted C₁-C₃ alkyl, substituted orunsubstituted cyclopropyl, substituted or unsubstituted —(C₁-C₃alkyl)-cyclopropyl, substituted or unsubstituted —CH═CH₂, substituted orunsubstituted —C≡C-cyclopropyl, substituted or unsubstituted phenyl,substituted or unsubstituted benzyl, —OH, —CH₂OH, —CF₃, —CF₂CF₃, —Cl,—F, —I, —CN, —CH₂CN, —NH₂, or —CH₂— tetrazolyl.
 16. The compound or saltof claim 14, wherein X¹ is —CR⁸R⁹—, —O—, or —NH—; and X² is —S—.
 17. Thecompound or salt of claim 14, wherein the compound is a compound offormula (Ib-1)

wherein R^(a) is —R⁴, —OR⁴, or —NR⁵R⁶, each of which R⁴, R⁵, and R⁶ issubstituted or unsubstituted; R^(b) and R^(c) are the same or differentand each is H or substituted or unsubstituted C₁-C₄ alkyl; each R² isthe same or different and each is hydrogen, hydroxyl, C₁-C₈ alkyl, C₂-C₈alkenyl, C₃-C₆ cycloalkyl, C₁-C₈ alkoxy, C₃-C₆ cycloalkyloxy, aryloxy,halo, C₁-C₈ haloalkoxy, C₁-C₈ haloalkyl, haloaryl, haloaryloxy, —CN,—NO₂, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁵R⁶, —NR⁵C(O)R⁴, —(CH₂)_(q)NR⁵(SO₂)R⁴,—(CH₂)_(q)NR⁵C(O)R⁴, —(CH₂)_(q)NR⁷C(O)NR⁵R⁶, —(CH₂)_(q)NR⁵R⁶,—(CH₂)_(q)SO₂NR⁵R⁶, —(CH₂)_(q)SO₂R⁴, —(CH₂)_(q)aryl,—(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl, each of which R²except hydrogen, hydroxyl, halo, —CN, and —NO₂ is substituted orunsubstituted; R³ is halo, —C(O)R⁴, C₂-C₈ alkynyl, haloaryl,—(CH₂)_(q)aryl, —(CH₂)_(q)heteroaryl, or —(CH₂)_(q)heterocycloalkyl,each of which R³ is substituted or unsubstituted; each R⁴, R⁵, R⁶, R⁷,R⁸, and R⁹ is the same or different and each is hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, or heterocycloalkyl,each of which C₁-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₆ cycloalkyl, aryl,heteroaryl, or heterocycloalkyl is substituted or unsubstituted; R¹⁰ ishydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkylalkyl, hydroxyl, hydroxyalkyl, C₁-C₈ alkoxy, C₁-C₈haloalkyl, halo, aryl, arylalkyl, heteroarylalkyl, —CN, —CO₂R⁴, —NR⁵R⁶,or —SO₂R⁴, each of which R¹⁰ except hydrogen, hydroxyl, halo, and —CN issubstituted or unsubstituted; X¹ is a bond, —CR⁸R⁹—, —NR⁵—, —O—, —SO—,or —SO₂—, or —S—, each of which R⁵, R⁸, and R⁹— is substituted orunsubstituted; X³ is CH or N; and m and q are the same or different andeach is 0 or an integer from 1-5.
 18. A compound selected from Table 7or salt thereof: TABLE 7 Inhibi- tory Ex- activ- am- ity ple CmpdCompound name IC₅₀ Meth- ID Structure and physical data (μM) od 19

2-(3-phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.21 (s,2H), 7.80-7.71 (m, 2H), 7.72-7.63 (m, 2H), 7.52-7.37 (m, 5H), 7.28 (s,2H), 4.15 (s, 2H); MS (M + H)⁺ = 441 +++ 28 20

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ13.20 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H),7.80- 7.74 (m, 2H), 7.74- 7.67 (m, 2H), 7.57 (d, J = 7.6 Hz, 3H), 7.50-7.42 (m, 4H), 7.37 (dd, J = 8.4, 6.3 Hz, 1H), 7.30 (s, 2H), 4.21 (s,2H); MS (M + H)⁺ = 517 +++ 29 21

2-(3-([1,1′-biphenyl]- 3-yl)-4-bromo-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.93(s, 1H), 8.28 (s, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 7.7, 1.5Hz, 1H), 7.79 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (dd, J = 7.5, 1.7 Hz,2H), + 30 7.63 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.40 (t, J= 7.4 Hz, 1H); MS (M + H)⁺ = 427 22

2-(3-([1,1′-biphenyl]- 3-yl)-1H-pyrazol-1- yl)thiazole-4- carboxylicacid, TFA (M + H)⁺ = 348 + 31 23

2-(3-(3,4- difluorophenyl)-1H- pyrrolo[2,3-b]pyridin- 1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 358 − 32 24

2-(5-hydroxy-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid, TFA MS (M + H)⁺ = 459 ++ 33 25

2-(3-(3,4- difluorophenyl)-1H- pyrazolo[3,4- b]pyridin-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.88-8.78 (m,2H), 8.33 (s, 1H), 8.15 (ddd, J = 11.7, 7.7, 2.2 Hz, 1H), 8.05- 7.97 (m,1H), 7.68 (dt, J = 10.8, 8.5 Hz, 1H), 7.60 (dd, J = 8.1, 4.6 Hz, 1H); MS(M + H)⁺ = 359 − 34 26

2-(3-(4- sulfamoylbenzyl)-1H- pyrrolo[2,3-b]pyridin- 1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 8.46 (dd, J =4.8, 1.5 Hz, 1H), 8.19 (s, 1H), 8.09 (dd, J = 7.8, 1.5 Hz, 1H), 8.07 (s,1H), 7.80-7.72 (m, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 7.9, 4.8Hz, 1H), 7.27 (s, 2H), 4.23 (s, 2H); MS (M + H)⁺ = 415 ++ 35 27

2-(4-(4- (methylsulfonyl) benzyl)-3-phenyl-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.34 (s,1H), 8.23 (d, J = 1.7 Hz, 1H), 7.86-7.79 (m, 2H), 7.70-7.62 (m, 2H),7.53-7.37 (m, 5H), 4.19 (s, 2H), 3.17 (s, 3H); MS (M + H)⁺ = 440 − 36 28

2-(3-phenyl-4-(4- (trifluoromethyl) benzyl)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.33 (s,1H), 8.23 (s, 1H), 7.69- 7.59 (m, 4H), 7.50- 7.36 (m, 5H), 4.18 (s, 2H);MS (M + H)⁺ = 430 − 37 29

2-(3-([1,1′-biphenyl]- 3-yl)-1H-pyrrolo[2,3- b]pyridin-1- yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H), 8.68 (s,1H), 8.57 (d, J = 4.7 Hz, 1H), 8.55-8.50 (m, 1H), 8.28 (s, 1H), 8.07 (d,J = 2.0 Hz, 1H), 7.83 (m, 3H), 7.68 (d, J = 7.7 Hz, 1H), 7.61 (t, J =7.6 Hz, 1H), 7.54-7.44 (m, 3H), 7.43-7.35 (m, 1H); MS (M + H)⁺ = 398 −38 30

2-(5-(morpholine-4- carbonyl)-3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.20(s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.73 (d,J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.43 (d, J =8.6 Hz, 1H), 7.25 (s, 2H), 4.21 (s, 2H), 3.76-3.34 (m, 8H); MS (M + H)⁺= 527 + 39 31

2-(5-fluoro-3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4- carboxylicacid ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.40 (dd, J = 9.2, 4.5Hz, 1H), 8.19 (d, J = 1.0 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.0 Hz,2H), 7.56 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 9.2, 2.6 Hz, 1H), 7.27-7.18(m, 3H), 4.16 (s, 2H); MS (M + H)⁺ = 432 ++ 40 32

2-(5- (morpholinomethyl)- 3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.11(s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.77 (s, 1H), 7.75-7.69 (m, 2H), 7.55- 7.49 (m, 2H), 7.45 (d, J = 1.8 Hz, 1H), 7.32 (dd, J= 8.5, 1.6 Hz, 1H), 7.23 (s, 2H), 4.17 (s, 2H), 3.58- 3.46 (m, 6H),2.35- 2.23 (m, 4H); MS (M + H)⁺ = 513 + 41 33

2-(3-phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 8.71 (s, 1H),8.28 (s, 1H), 7.86- 7.81 (m, 2H), 7.81- 7.75 (m, 2H), 7.48- 7.35 (m,3H), 7.33- 7.29 (m, 2H), 7.27 (s, 2H); MS (M + H)⁺ = 443 +++ 42 34

2-(3-(4- sulfamoylbenzyl)-1H- pyrrolo[3,2-c]pyridin- 1-yl)thiazole-4-carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J = 1.0 Hz,1H), 8.46 (d, J = 5.8 Hz, 1H), 8.27 (s, 1H), 8.21 (dd, J = 5.8, 1.0 Hz,1H), 7.95 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H),7.23 (s, 2H), 4.25 (s, 2H) (acid OH not shown); MS (M + H)⁺ = 415 ++ 4335

2-(3-(4- sulfamoylbenzyl)-1H- indazol-1-yl)thiazole- 4-carboxylic acid¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H),8.18 (s, 1H), 7.80 (dd, J = 8.0, 1.0 Hz, 1H), 7.77-7.72 (m, 2H), 7.67(ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.59-7.51 (m, 2H), 7.35 (ddd, J = 8.1,7.0, 0.9 Hz, 1H), 7.27 (s, 2H), 4.49 (s, 2H); MS (M + H)⁺ = 415 + 44 36

2-(3-(4- sulfamoylbenzyl)-5- ((tetrahydro-2H- pyran-4-yl)oxy)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ8.22 (d, J = 8.9 Hz, 1H), 8.04 (s, 1H), 7.74 (d, J = 3.6 Hz, 2H), 7.71(d, J = 1.9 Hz, 1H), 7.58- 7.50 (m, 2H), 7.23 (s, 2H), 7.06 (d, J = 2.4Hz, 1H), 7.01 (dd, J = 9.0, 2.4 Hz, 1H), 4.57- 4.41 (m, 1H), 4.14 (s,2H), 3.83 (dt, J = 11.7, 4.4 Hz, 2H), ++ 3.44 (ddd, J = 11.8, 9.5, 2.8Hz, 2H), 1.90 (dd, J = 13.1, 3.5 Hz, 2H), 1.54 (ddd, J = 13.0, 8.8, 4.0Hz, 2H) (acid OH not shown); MS (M + H) = 514 37

2-(6-(morpholine-4- carbonyl)-3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH₃ ¹H NMR (400 MHz, DMSO-d₆) δ8.45 (dd, J = 1.4, 0.7 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.75-7.67(m, 2H), 7.58 (dd, J = 8.1, 0.7 Hz, 1H), 7.56- 7.51 (m, 2H), 7.28- 7.16(m, 3H), 4.19 (s, 2H), 3.54 (d, J = 41.1 Hz, 8H) (acid OH not shown); MS(M + H)⁺ = 527 + 46 38

2-(5-amino-3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid MS (M + H)⁺ = 492 +++ 12, 18 39

2-(3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.47 (d, J = 1.2 Hz, 1H), 7.87- 7.66(m, 2H), 7.69- 7.46 (m, 2H), 7.48- 7.19 (m, 5H), 4.24 (s, 2H); MS (M +H)⁺ = 545 +++ 14, 18 40

2-(3-([1,1′-biphenyl]- 3-yl)-5-amino-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.06 (s, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.79- 7.74 (m, 2H), 7.70- 7.62(m, 2H), 7.59- 7.47 (m, 2H), 7.46- 7.32 (m, 7H), 7.29 (s, 2H), 6.94 (s,2H), 4.05 (s, 2H); (M + H)⁺ = 532 +++ 12, 18 41

2-(3-(3,4- difluorophenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.86-7.62 (m, 2H), 7.55 (q, J = 5.7, 4.9 Hz, 2H), 7.47-7.38 (m, 2H), 7.31 (s, 1H), 4.18 (s, 2H); (M + H)⁺ = 477 +++ 28 42

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H), 7.77 (tt,J = 6.6, 1.5 Hz, 3H), 7.67 (q, J = 1.6 Hz, 1H), 7.62-7.28 (m, 13H), 4.27(s, 2H); (M + H)⁺ = 589 +++ 14, 18 43

2-(3-(3,4- difluorophenyl)-5- iodo-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.23 (s, 1H), 8.41 (d, J = 1.1 Hz, 1H), 7.83- 7.65 (m, 2H), 7.63- 7.47(m, 2H), 7.42- 7.35 (m, 1H), 7.32- 7.25 (m, 4H), 4.15 (s, 2H); (M + H)⁺= 603 +++ 13, 18 44

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.27 (s, 1H), 8.46 (d, J = 0.9 Hz, 1H), 7.79- 7.66 (m, 2H), 7.58- 7.41(m, 5H), 7.30 (s, 3H), 7.33-7.26 (m, +++ 14, 18 1H), 4.23 (s, 2H); (M +H)⁺ = 509 45

2-(5-iodo-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.37 (d, J =1.2 Hz, 1H), 7.75- 7.67 (m, 2H), 7.57- 7.49 (m, 2H), 7.51- 7.36 (m, 3H),7.31- 7.24 (m, 4H), 4.12 (s, 2H); (M +H)⁺ = 567 +++ 13, 18 46

2-(5-cyclopropyl-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.11 (s, 1H), 8.32 (s, 1H), 7.74-7.70 (m, 2H), 7.53-7.49 (m, 2H),7.43-7.37 (m, 3H), 7.31-7.26 (m, 4H), 4.14 (s, 2H), 2.25 (tt, J = 8.5,5.6 Hz, 1H), 1.02-0.92 (m, 2H), 0.71-0.62 (m, 2H); (M + H)⁺ = 481 +++112 47

2-(5-methyl-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29-8.19(m, 1H), 7.78-7.65 (m, 2H), 7.53 (dq, J = 6.8, 1.3 Hz, 2H), 7.49- 7.33(m, 3H), 7.32- 7.23 (m, 4H), 4.08 (s, 2H), 2.67 (d, J = 1.1 Hz, 3H);(M + H)⁺ = 455 +++ 49 48

2-(3-phenyl-4-((4- sulfamoylphenyl) amino)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.57 (s, 1H),8.25 (d, J = 2.4 Hz, 2H), 7.82 (dt, J = 8.1, 1.3 Hz, 3H), 7.55 (dd, J =8.7, 1.2 Hz, 3H), 7.48-7.33 (m, 4H), 6.98 (s, 2H), 6.85- 6.76 (m, 2H);(M + H)⁺ = 442 +++ 27 49

4-(((5-hydroxy-3- phenyl-1H-pyrazol-4- yl)methyl)amino)benzenesulfonamide (M + H)⁺ = 345 − 149 50

2-(5-carbamoyl-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 466 +++ 17, 18 51

2-(3-([1,1′-biphenyl]- 3-yl)-4-((4- sulfamoylphenyl)amino)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid. (M + H)⁺ = 518 +++27 52

2-(3-([1,1′-biphenyl]- 3-yl)-5-cyclopropyl-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.12 (s, 1H), 7.80-7.73 (m, 2H), 7.73-7.59 (m, 2H), 7.60-7.47 (m, 2H),7.42 (d, J = 4.3 Hz, 4H), 7.43- 7.28 (m, 5H), 4.19 (s, 2H), 2.30 (tt, J= 8.6, 5.6 Hz, 1H), 1.04- 0.95 (m, 2H), 0.73- +++ 112 0.64 (m, 2H); (M +H)⁺ = 557 53

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 493 ++ 147 54

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 533 ++ 147 55

2-(3-(2′-fluoro-[1,1′- biphenyl]-3-yl)-5- hydroxy-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ =551 ++ 147 56

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- amino-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ = 560 + 12, 18 57

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)-5-methylthiazole-4- carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s,1H), 7.81-7.65 (m, 2H), 7.48 (dq, J = 6.8, 1.3 Hz, 2H), 7.49- 7.26 (m,5H), 7.24 (s, 2H), 6.82 (s, 2H), 3.97 (s, 2H), 2.68 (d, J = 1.2 Hz, 3H),2.52 (d, J = 1.2 Hz, 1H); (M + H)⁺ = 470 ++ 148 58

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ = 484 + 12 59

2-(5-(cyanomethyl)-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ8.28 (s, 1H), 7.70-7.63 (m, 2H), 7.59-7.49 (m, 2H), 7.46-7.34 (m, 3H),7.30-7.22 (m, 4H), 4.67 (s, 2H), 4.22 (s, 2H); (M + H)⁺ = 480 ++ 19, 2060

2-(3-(3,4- difluorophenyl)-5- methoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 507 ++ 73 61

2-(3-(3,4- difluorophenyl)-5- ethoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid ++ 73 62

2-(3-phenyl-5- (trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid (M + H)⁺ = 340 + 150 63

2-(3-(2′-fluoro-[1,1′- biphenyl]-3-yl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 382 − 147 64

2-(3-(3,4- difluorophenyl)-5- (hydroxymethyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid. (M + H)⁺ = 338 − 151 65

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid − 147 66

2-(5-hydroxy-3- methyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid − 147 67

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- carbamoylbenzyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147 68

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- carboxybenzyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 69

2-(3-(3- bromophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid + 147 70

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxamide − 152 71

2-(5-carboxy-3-(3,4- difluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid − 151 72

4-((1-(4-(1H-tetrazol- 5-yl)thiazol-2-yl)-3- ([1,1′-biphenyl]-3-yl)-5-hydroxy-1H- pyrazol-4- yl)methyl) benzenesulfonamide + 153 73

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate + 147 74

2-(5-(cyanomethyl)-3- (3,4-difluorophenyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid + 19, 20 75

2-(5-((1H-tetrazol-5- yl)methyl)-3-(3,4- difluorophenyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid + 21, 20 76

2-(3-phenyl-4-(4- sulfamoylphenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 427 + 69 77

ethyl 2-(3-phenyl-4- (4-sulfamoylbenzyl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl) thiazole-4- carboxylate (M + H)⁺ = 537 + 14 78

2-(5-iodo-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxamide + 152 79

2-(3-phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxamide + 152 80

2-(3-phenyl-5- (pyridin-3-ylamino)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 533 + 154 81

2-(5-hydroxy-3- (naphthalen-1-yl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid + 69 82

2-(5-hydroxy-3- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid + 147 83

4-((5-amino-1-(6- chloropyridazin-3-yl)- 3-phenyl-1H-pyrazol-4-yl)methyl) benzenesulfonamide + 148 84

4-((5-amino-1-(3- methylbenzoyl)-3- phenyl-1H-pyrazol-4- yl)methyl)benzenesulfonamide + 148 85

4-((5-amino-1-(3- fluorobenzoyl)-3- phenyl-1H-pyrazol-4- yl)methyl)benzenesulfonamide + 148 86

4-((5-amino-1-(4- methylthiazol-2-yl)-3- phenyl-1H-pyrazol-4- yl)methyl)benzenesulfonamide + 148 87

2-(5-((1H-tetrazol-5- yl)methyl)-3-phenyl- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 523 + 21, 18 88

4-((1-(4- (hydroxymethyl) thiazol-2- yl)-3-phenyl-5-(trifluoromethyl)-1H- pyrazol-4- yl)methyl) benzenesulfonamide + 22 89

2-(3-(6- fluoronaphthalen-1- yl)-5-hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid − 69 90

2-(3-phenyl-4-((4- sulfamoylpiperazin-1- yl)methyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 449 + 155 91

2-(5-hydroxy-3- phenyl-1H-pyrazol-1- yl)thiazole-4- carboxylic acid −147 92

2-(5-hydroxy-3-(3- (methylsulfonyl) phenyl)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid − 147 93

2-(5-hydroxy-3-(3- morpholinophenyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid − 147 94

2-(3-(4-fluoro-3- (methylsulfonyl) phenyl)-5-hydroxy-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid − 147 95

2-(3-(3,5- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 96

2-(3-(2,3- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 97

2-(3-(2,4- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 98

1- ((ethoxycarbonyl)oxy) ethyl 2-(3-(3,4- difluorophenyl)-5-(1-((ethoxycarbonyl)oxy) ethoxy)-1H-pyrazol- 1-yl)thiazole-4- carboxylate −156 99

(pivaloyloxy)methyl 2-(3-(4-fluorophenyl)- 5-((pivaloyloxy)methoxy)-1H-pyrazol-1- yl)thiazole-4- carboxylate − 156 100

2-(3-(2,6- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 101

3-(3-fluoro-4- (methylsulfonyl) phenyl)-1-(4- (hydroxymethyl)thiazol-2-yl)- 1H-pyrazol- 5-ol − 147 102

2-(3-(2,5- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 103

2-(3-(4-fluoro-3- (methylsulfonamido) phenyl)-5-hydroxy-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid − 147 104

2-(3-(3-benzyl-4- fluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid − 147 105

1- ((ethoxycarbonyl)oxy) ethyl 2-(3-(3,4- difluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylate − 156 106

2-morpholinoethyl 2- (3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylate − 156 107

2,3-dihydro-1H-inden- 5-yl 2-(3-(3,4- difluorophenyl)-5-((dimethylcarbamoyl) oxy)-1H-pyrazol-1- yl)thiazole-4- carboxylate − 156108

2,3-dihydro-1H-inden- 5-yl 2-(3-(3,4- difluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylate − 156 109

(isobutyryloxy)methyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylate − 156 110

2-(3-(3-(N- benzylsulfamoyl)-4- fluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 111

2-(3-(4- (cyclopropane- sulfonamido)-3- fluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147 112

2-(3-(4-(2- (cyclopropane- sulfonamido)ethyl)- 3-fluorophenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid − 147 113

2-(4-benzyl-3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol-1-yl)thiazole-4- carboxylic acid − 147 114

2-(3-(4-fluoro-3-(N- methylsulfamoyl) phenyl)-5-hydroxy- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid - 147 115

methyl 2-(3,4- difluorophenyl)-5- oxo-4,5- dihydropyrazolo[1,5-a]thieno[3,2- e]pyrimidine-6- carboxylate (M + H)⁺ = 362 − 157 116

2-(3,4- difluorophenyl)-5- oxo-4,5- dihydropyrazolo[1,5- a]thieno[3,2-e]pyrimidine-6- carboxylic acid (M + H)⁺ = 348 − 157 117

tert-butyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(3-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate − 69 118

tert-butyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-4-phenyl-1H-pyrazol-1-yl)thiazole- 4-carboxylate - 69 119

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indazol- 1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 374 − 69 120

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indazol- 1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 352 − 34 121

ethyl 2-(3-(3,4- difluorophenyl)-5- hydroxy-1H-pyrazol- 1-yl)thiazole-4-carboxylate (M + H)⁺ = 352 − 147 122

2-(3-(4-fluoro-3-(2- (methylsulfonamido) ethyl)phenyl)-5-hydroxy-1H-pyrazol- 1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 427 −147 123

ethyl 2-(5-amino-3- (3,4-difluorophenyl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ = 520 + 12 124

2-(3-([1,1′-biphenyl]- 3-yl)-5-hydroxy-4-(4- (N- methylsulfamoyl)benzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 547 − 69125

2-(3-(3,4- difluorophenyl)-7- hydroxy-1H-indol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 373 − 32 126

2-(4-acetamido-5- hydroxy-3-phenyl-1H- pyrazol-1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 345 − 33 127

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)thiazole- 4-carboxamide − 152 128

4-((5-amino-1-(6-oxo- 1,6-dihydropyridazin- 3-yl)-3-phenyl-1H-pyrazol-4- yl)methyl) benzenesulfonamide − 148 129

ethyl 3-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)benzoate − 148 130

3-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)benzoicacid − 148 131

4-((5-amino-1-(4- (hydroxymethyl) thiazol-2-yl)-3-phenyl- 1H-pyrazol-4-yl)methyl) benzenesulfonamide − 148 132

4-((5-((1H-tetrazol-5- yl)methyl)-1-(4- (hydroxymethyl)thiazol-2-yl)-3-phenyl- 1H-pyrazol-4- yl)methyl) benzenesulfonamide (M +H)⁺ = 509 − 22 133

methyl)-3-phenyl-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylate (M + H)⁺ = 537 − 21 134

ethyl 2-(5-((1H- tetrazol-5-yl)methyl)- 3-phenyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ = 551− 21 135

ethyl 2-(5- (cyanomethyl)-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ = 508 − 19 136

2-(3-phenyl-4-(4- sulfamoylbenzamido)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 449 − 158 137

4-((5-amino-3-phenyl- 1-(4-(trifluoromethyl) thiazol-2-yl)-1H-pyrazol-4-yl)methyl) benzenesulfonamide − 148 138

2-(3-phenyl-4- ((piperazine-1- sulfonamido)methyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 449 − 155 139

2-(3-phenyl-4-(((4- sulfamoylphenyl) amino)methyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 456 − 155 140

ethyl 6-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)pyridazine-3- carboxylate − 148 141

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate (M + H)⁺ =585 − 14 142

2-(3-phenyl-4-((4- sulfamoylbenzyl) amino)-1H-pyrazol-1- yl)thiazole-4-carboxylic acid (M + H)⁺ = 456 − 158 143

4-((5-amino-1-(5- amino-1-methyl-1H- pyrazole-4-carbonyl)-3-phenyl-1H-pyrazol- 4-yl)methyl) benzenesulfonamide − 148 144

6-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)picolinicacid + 148 145

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)isonicotinic acid − 148 146

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)-5-methylthiazole-4- carboxylate (M + H)⁺ = 498 − 148 147

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)-5-methylthiazole-4- carboxylic acid (M + H)⁺ = 470 + 148 148

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 456 + 148 149

(5-methyl-2-oxo-1,3- dioxol-4-yl)methyl 2- (3-phenyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate ++ 156 150

4-((5-amino-1-(1H- indole-7-carbonyl)-3- phenyl-1H-pyrazol-4- yl)methyl)benzenesulfonamide − 148 151

ethyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)oxazole- 4-carboxylate (M + H)⁺ = 468 + 148 152

4-((5-amino-1-(4- hydroxypyrimidin-2- yl)-3-phenyl-1H- pyrazol-4-yl)methyl) benzenesulfonamide − 148 153

2-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)oxazole-4-carboxylic acid (M + H)⁺ = 440 ++ 148 154

4-((3-phenyl-1-(4- (2,2,2-trifluoro-1- hydroxyethyl)thiazol-2-yl)-1H-pyrazol-4- yl)methyl) benzenesulfonamide 1H NMR (400 MHz,DMSO-d6) δ 8.21 (d, J = 0.8 Hz, 1H), 7.76- 7.61 (m, 4H), 7.57 (d, J =0.7 Hz, 1H), 7.49-7.35 (m, 5H), 7.26 (s, 2H), 6.99 (d, J = 6.3 Hz, 1H),5.27- 5.15 (m, 1H), 4.14 (s, 2H); (M + H)⁺ = 495 ++ 159 155

2-(3,5-diphenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.23 (s,1H), 7.75-7.67 (m, 0H), 7.66-7.55 (m, 4H), 7.40 (s, 4H), 7.47- 7.30 (m,4H), 7.30- 7.15 (m, 5H), 3.98 (s, 2H); (M + H)⁺ = 517 +++ 15 156

2-(3-phenyl-5- (pyridin-4-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ12.87 (s, 1H), 8.64-8.57 (m, 2H), 8.23 (s, 1H), 7.66-7.54 (m, 4H),7.47-7.34 (m, 5H), 7.25-7.16 (m, 4H), 4.05 (q, J = 5.2 Hz, 1H), 4.01 (s,2H), + 15 3.14 (d, J = 5.2 Hz, 2H); (M + H)⁺ = 518 157

2-(3-phenyl-5- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ8.71- 8.61 (m, 2H), 8.22 (s, 1H), 8.00 (ddd, J = 7.9, 2.2, 1.7 Hz, 1H),7.66-7.57 (m, 4H), 7.52 (ddd, J = 7.9, 5.0, 0.9 Hz, 1H), 7.47- 7.34 (m,3H), 7.25- ++ 15 7.17 (m, 4H), 4.01 (s, 2H); (M + H)⁺ = 518 158

2-(3-isopropyl-5- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 483 + 49 159

2-(5-isopropyl-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (600 MHz, DMSO-d6) δ13.14 (s, 1H), 8.28 (s, 1H), 7.74-7.68 (m, 2H), 7.51-7.45 (m, 2H),7.42-7.34 (m, 3H), 7.31-7.25 (m, 4H), 4.21-4.12 (m, 1H), 4.15 (s, 2H),1.28- 1.24 (m, 6H); (M + H)⁺ = 483 ++ 49 160

2-(5- (cyclopropylethynyl)- 3-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.13 (s, 1H), 8.31 (s, 1H), 7.76-7.68 (m, 2H), 7.65-7.55 (m, 2H),7.50-7.37 (m, 3H), 7.36-7.21 (m, 4H), 4.17 (s, 2H), 1.60 (tt, J = 7.7,5.3 Hz, 1H), 1.00-0.86 (m, 4H); (M + H)⁺ = 505 +++ 16 161

4-((3-([1,1′-biphenyl]- 3-yl)-1H-pyrazol-4- yl)amino) benzenesulfonamide(M + H)⁺ = 391 − 25 162

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-4-((4- sulfamoylphenyl)amino)-1H-pyrazol-1- yl)thiazole-4- carboxylate (M + H)⁺ = 546 + 26 163

ethyl 2-(3- cyclopropyl-5-phenyl- 4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 511 − 33 164

ethyl 2-(5- cyclopropyl-3-phenyl- 4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 511 + 33 165

cyclopropyl-5-phenyl- 4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 483 + 33 166

2-(5-cyclopropyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s,1H), 8.35 (s, 1H), 7.83-7.71 (m, 4H), 7.45-7.31 (m, 3H), 7.29-7.15 (m,4H), 3.31 (s, 2H), 2.63 (tt, J = 8.5, 5.5 Hz, 1H), 0.99-0.80 (m, 4H);(M + H)⁺ = 483 +++ 33 167

2-(3-phenyl-4-(4- sulfamoylbenzyl)-5- vinyl-1H-pyrazol-1- yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.32 (s, 1H),7.80-7.72 (m, 2H), 7.65 (dd, J = 18.1, 11.9 Hz, 1H), 7.59- 7.50 (m, 2H),7.55- 7.26 (m, 8H), 5.63- 5.54 (m, 1H), 5.45 (dd, J = 18.1, 1.1 Hz, 1H),4.21 (s, 2H); (M + H)⁺ = 467 +++ 15 168

ethyl 2-(3- cyclopentyl-5-phenyl- 4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 539 − 33 169

ethyl 2-(5- cyclopentyl-3-phenyl- 4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylate (M + H)⁺ = 539 − 33 170

2-(3-cyclopentyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 511 + 33 171

2-(5-cyclopentyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 511 ++ 33 172

2-(3-cyclohexyl-5- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M + H)⁺ = 525 + 33 173

2-(5-cyclohexyl-3- phenyl-4-(4- sulfamoylphenoxy)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid (M+ H)⁺ = 525 + 33 174

2-(3-cyclopentyl-5- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 508 + 49 175

2-(5-cyclopentyl-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 508 ++ 49 176

2-(3-cyclohexyl-5- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 523 + 49 177

2-(5-cyclohexyl-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M+ H)⁺ = 523 + 49 178

2-(5-(oxiran-2-yl)-3- phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 483 + 160 179

2-(3-phenyl-5- (phenylethynyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 541 + 16 180

ethyl 2-(5-([1,1′- biphenyl]-3-yl)-3- cyclopropyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate (M+ H)⁺ = 585− 49 181

ethyl 2-(3-([1,1′- biphenyl]-3-yl)-5- cyclopropyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylate 1H NMR (400MHz, DMSO-d6) δ 8.40 (s, 1H), 7.80-7.73 (m, 2H), 7.73-7.47 (m, 4H),7.47-7.28 (m, 9H), 4.33 (q, J = 7.1 Hz, 2H), 4.20 (s, 2H), 3.35-3.25 (m,1H), 2.25 (tt, J = 8.5, 5.6 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.06-0.96 (m, 2H), 0.75- − 49 0.65 (m, 2H); (M + H)⁺ = 585 182

cyclopropyl-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid (M + H)⁺ = 575 + 49 183

2-(3-([1,1′-biphenyl]- 3-yl)-5-cyclopropyl-4- (2-fluoro-4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.34 (s, 1H), 7.70 (dt, J = 6.6, 2.1Hz, 1H), 7.62 (dt, J = 2.7, 1.4 Hz, 2H), 7.61- 7.49 (m, 4H), 7.49- 7.40(m, 6H), 7.39- 7.33 (m, 1H), 7.28- 7.19 (m, 1H), 4.14 (s, 2H), 2.24 (tt,J = 8.5, 5.6 Hz, 1H), 1.13- 0.90 (m, 2H), 0.78- +++ 49 0.60 (m, 2H);(M + H)⁺ = 575 184

2-(5-([1,1′-biphenyl]- 3-yl)-3-cyclopropyl-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 557 + 49 185

2-(5-benzyl-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.66-7.53(m, 4H), 7.45-7.33 (m, 3H), 7.28-7.06 (m, 10H), 4.69 (s, 2H), 4.18 (s,2H), 4.11-4.03 (m, 1H), 3.17 (d, J = 4.6 Hz, 2H); (M+ H)⁺ = 531 ++ 49186

2-(5-([1,1′-biphenyl]- 3-yl)-3-cyclopropyl-4- (4- sulfamoylphenoxy)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M + H)⁺ = 559 + 33 187

2-(3-([1,1′-biphenyl]- 3-yl)-5-cyclopropyl-4- (4-sulfamoylphenoxy)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ13.17 (s, 1H), 8.36 (s, 1H), 7.93 (td, J = 1.8, 0.5 Hz, 1H), 7.85-7.71(m, 3H), 7.66 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.56-7.32 (m, 6H),7.30-7.21 (m, 4H), 2.73-2.61 (m, 1H), 1.02-0.90 (m, 2H), 0.93-0.83 (m,+++ 33 2H); (M + H)⁺ = 559 188

2-(3- (cyclopropylmethyl)- 5-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 495 ++ 141 189

2-(5- (cyclopropylmethyl)- 3-phenyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ = 495 +++ 141 190

methyl 2-(5-amino-3- phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)-4-(trifluoromethyl) pyrimidine-5- carboxylate − 148 191

6-(5-amino-3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)pyridazine-3- carboxylic acid − 148 192

2-(6- (morpholinomethyl)- 3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH3 1H NMR (400 MHz, DMSO-d₆) δ8.13 (s, 1H), 7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.56-7.50 (m, 2H),7.50-7.46 (m, 1H), 7.45 (s, 1H) 7.23 (s, 2H), 7.14 (dd, J = 8.1, 1.4 Hz,1H), 4.15 (s, 2H), 3.55 (dd, J = 8.9, 4.4 Hz, 6H), 2.34 (t, J = 4.6 Hz,4H) (acid ++ 41 OH not shown); MS (M + H)⁺ = 513 193

2-(4- (morpholinomethyl)- 3-(4- sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4- carboxylic acid, NH3 ¹H NMR (400 MHz, DMSO-d₆) δ8.27 (d, J = 8.4 Hz, 1H), 7.79- 7.70 (m, 2H), 7.48 (s, 1H), 7.46 (s,1H), 7.41-7.34 (m, 2H), 7.31-7.23 (m, 3H), 7.06 (dd, J = 7.3, 1.0 Hz,1H), 4.51 (s, 2H), 3.51 (dd, J = 9.5, 4.9 Hz, 6H), 2.35-2.21 (m, 4H)(acid OH not ++ 41 shown); MS (M+ H)⁺ = 513 194

2-(5-(2-fluorobenzyl)- 3-(4-sulfamoylbenzyl)- 1H-indol-1-yl) thiazole-4-carboxylic acid, NH3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.23- 8.17 (m, 1H),8.03 (s, 1H), 7.74 (s, 1H), 7.73-7.67 (m, 2H), 7.52-7.45 (m, 2H), 7.42(d, J = 1.6 Hz, 1H), 7.23 (m, 5H), 7.17-7.05 (m, 2H), 4.12 (s, 2H), 4.02(s, 2H) (acid OH not shown); MS (M + H)⁺ = 522 ++ 40 195

2-(5-(2-fluorophenyl)- 3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 8.42 (dd, J =8.6, 0.6 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.77-7.68 (m, 3H),7.59-7.54 (m, 3H), 7.52 (td, J = 7.8, 1.7 Hz, 1H), 7.39 (tdd, J = 7.8,5.1, 1.8 Hz, 1H), 7.33-7.24 (m, 2H), 7.21 (s, 2H), +++ 40 4.22 (s, 2H);MS (M + H)⁺ = 508 196

2-(3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4- carboxylic acid ¹HNMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 8.34 (dt, J = 8.4, 0.9 Hz, 1H),8.18 (s, 1H), 7.83 (s, 1H), 7.75-7.67 (m, 2H), 7.57-7.48 (m, 3H), 7.37(ddd, J = 8.4, 7.1, 1.2 Hz, 1H), 7.22 (s, 2H), 7.21-7.16 (m, 1H), 4.18(s, 2H); MS (M + H)⁺ = 414 ++ 40 197

2-(3-(4- sulfamoylbenzyl)-6- (trifluoromethyl)-1H-indol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 513.20 (s, 1H), 8.79 (dd, J = 1.7, 0.9 Hz, 1H), 8.20 (s, 1H), 8.11 (s,1H), 7.78-7.68 (m, 3H), 7.59-7.49 (m, 3H), 7.23 (s, 2H), 4.23 (s, 2H);MS (M + H)⁺ = 482 ++ 40 198

2-(4-(2-fluorobenzyl)- 3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.34 (dd, J =8.4, 0.9 Hz, 1H), 8.18 (s, 1H), 7.75-7.70 (m, 2H), 7.69 (s, 1H),7.35-7.21 (m, 6H), 7.17 (ddd, J = 9.6, 8.2, 1.3 Hz, 1H), 7.04 (td, J =7.4, 1.3 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 6.78-6.71 (m, 1H), 4.17 (s,2H), ++ 40 4.14 (s, 2H); MS (M + H)⁺ = 522 199

2-(4-(4- (hydroxymethyl) benzyl)- 3-phenyl-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.20 (s,1H), 8.11 (s, 1H), 7.73- 7.65 (m, 2H), 7.50- 7.36 (m, 3H), 7.27- 7.15(m, 4H), 5.07 (t, J = 5.8 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 4.02 (s,2H); MS (M + H)⁺ = 392 − 28 200

2-(3-([1,1′-biphenyl]- 3-yl)-4-(4- (hydroxymethyl)benzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s,1H), 8.21 (d, J = 2.9 Hz, 2H), 7.83 (t, J = 1.8 Hz, 1H), 7.70 (ddt, J =7.7, 6.0, 1.4 Hz, 2H), 7.61-7.49 (m, 3H), 7.44 (s, 1H), 7.45-7.31 (m,2H), 7.29-7.17 (m, 4H), 5.09 (t, J = 5.8 Hz, + 29 1H), 4.45 (d, J = 5.3Hz, 2H), 4.09 (s, 2H); MS (M + H)⁺ = 468 201

2-(6-(hydroxymethyl)- 3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (s, 1H), 8.27-8.23 (m,1H), 8.19 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.74-7.69 (m, 2H),7.55-7.49 (m, 2H), 7.49-7.43 (m, 1H), 7.22 (s, 2H), 7.15 (dd, J = 8.1,1.4 Hz, 1H), 5.22 (t, J = 5.7 Hz, 1H), 4.59 (d, ++ 40 J = 4.6 Hz, 2H),4.16 (s, 2H); MS (M + H)⁺ = 444 202

2-(7-fluoro-3-(4- sulfamoylbenzyl)-1H- indol-1-yl)thiazole-4- carboxylicacid ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.37 (s, 1H), 7.72 (m,3H), 7.52 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.24 (s, 2H),7.21- 7.07 (m, 2H), 4.17 (s, 2H); MS (M + H)⁺ = 432 ++ 40 203

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2- cyclopropylethyl)-4-(4-su1famoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 +++ 49 204

2-(5-([1,1′-biphenyl]- 3-yl)-3-(2- cyclopropylethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 + 49 205

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2,2- difluorocyclopropyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR(400 MHz, DMSO-d6) δ 13.29- 12.98 (m, 1H), 8.34 (s, 1H), 7.78-7.73 (m,2H), 7.73-7.66 (m, 2H), 7.63-7.49 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.32(m, 3H), 7.30 (s, 2H), +++ 49 4.22 (s, 2H), 3.30- 3.24 (m, 1H), 2.24-1.98 (m, 1H), 1.81- 1.60 (m, 1H); (M + H)⁺ = 593 206

2-(5-([1,1′-biphenyl]- 3-yl)-3-(2,2- difluorocyclopropyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ =593 + 49 207

2-(3-([1,1′-biphenyl]- 3-yl)-5-((2,2- difluorocyclopropyl) methyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid ¹H NMR(400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.30 (s, 1H), 7.77-7.67 (m, 4H),7.61 (dt, J = 7.8, 1.4 Hz, 1H), 7.52 (td, J = 7.6, 0.8 Hz, 1H), 7.48-7.40 (m, 4H), 7.38- 7.33 (m, 3H), 7.30 (s, 2H), 4.19 (s, 2H), 3.40 (td,J = 19.2, 17.2, 7.3 Hz, 2H), 2.28-2.11 (m, 1H), +++ 49 1.55-1.32 (m,1H); (M + H)⁺ = 607 208

2-(5-([1,1′-biphenyl]- 3-yl)-3-((2,2- difluorocyclopropyl) methyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid (M + H)⁺ =607 + 49 209

2-(3-([1,1′-biphenyl]- 3-yl)-5-(2- cyclopropylethyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4- carboxylic acid (M +H)⁺ = 585 +++ 49 210

4-((1-(4-oxo-3,4- dihydrothieno[3,2- d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4- yl)methyl) benzenesulfonamide ¹H NMR (400 MHz,DMSO-d6) δ 12.79 (s, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H),7.74-7.68 (m, 2H), 7.68-7.62 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.34 (m,3H), 7.25 (s, 2H), 4.16 (s, 2H); MS (M + H)⁺ = 464 − 51 211

4-((1-(4- aminothieno[3,2- d]pyrimidin-7-yl)-3- phenyl-1H-pyrazol-4-yl)methyl) benzenesulfonamide, TFA ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (d,J = 4.9 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H),7.87 (s, 2H), 7.69 (m, 4H), 7.49- 7.30 (m, 5H), 7.26 (s, 2H), 4.17 (s,2H); MS (M + H)⁺ = 463 + 52 212

1-methyl-2-(3-phenyl- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)-1H-imidazole-5- carboxylic acid, TFA; MS (M + H)⁺ = 438 − 53 213

5-(3-phenyl-4-(4- sulfamoylbenzyl)-1H- pyrazol-1- yl)thiophene-3-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.45 (s,1H), 7.96 (d, J = 1.6 Hz, 1H), 7.73-7.66 (m, 2H), 7.63-7.55 (m, 3H),7.44-7.32 (m, 5H), 7.26 (s, 2H), 4.08 (s, 2H); MS (M + H)⁺ = 440 + 54214

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(1- methyl-1H-pyrazol-4-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29(s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.78-7.72 (m, 2H), 7.52 (dd, J = 9.6,1.8 Hz, 1H), 7.46 (dd, J = 8.0, 1.8 Hz, 1H), 7.40 (s, 2H), 7.34 (ddd, J= 8.5, 5.0, 2.2 Hz, 1H), 7.26 (dd, J = 11.0, 8.5 Hz, 1H), +++ 55 7.12(t, J = 7.8 Hz, 1H), 4.10 (s, 2H), 3.85 (s, 3H), 3.15 (d, J = 7.0 Hz,2H), 1.14- 1.01 (m, 1H), 0.37- 0.14 (m, 4H); MS (M + H)⁺ = 611 215

2-(5- (cyclopropylmethyl)- 3-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)-4- (2-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, TFA MS (M + H)⁺ = 626 +++ 56216

2-(3- (cyclopropylmethyl)- 5-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)-4- (2-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, TFA MS (M + H)⁺ = 626 − 56 217

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(1- methyl-1H-pyrazol-4-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 611 +++ 57 218

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(1- methyl-1H-pyrazol-4-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 611 − 57 219

2-(5- (cyclopropylmethyl)- 3-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, TFA MS (M + H)⁺ = 626 +++ 58220

2-(3- (cyclopropylmethyl)- 5-(3-(3,5- dimethylisoxazol-4-yl)-4-fluorophenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, TFA MS (M + H)⁺ = 626 − 58 221

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 +++ 59 222

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 − 59 223

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 +++ 60 224

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(4- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 − 60 225

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 NA 61 226

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 − 61 227

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 NMR (HCl salt) from YSM14-67 ¹HNMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.67 (t, J = 7.9Hz, 1H), 7.62 (dd, J = 7.6, 2.2 Hz, 1H), 7.58 (s, 2H), 7.50 (ddd, J =8.5, 4.8, 2.2 Hz, 1H), 7.34 (dd, J = 11.3, 8.6 +++ 62 Hz, 1H), 7.19 (dd,J = 11.3, 1.6 Hz, 1H), 7.13 (dd, J = 3.6, 0.9 Hz, 1H), 7.06 (dd, J =8.1, 1.6 Hz, 1H), 6.81 (dt, J = 3.6, 1.1 Hz, 1H), 4.14 (s, 2H), 3.15 (d,J = 6.9 Hz, 2H), 2.44 (d, J = 1.1 Hz, 3H), 1.19-1.03 (m, 1H), 0.39-0.28(m, 2H), 0.24-0.14 (m, 2H) 228

2-(3- (cyclopropylmethyl)- 5-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA MS (M + H)⁺ = 627 − 62 229

ethyl 2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylate ¹H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.55 (dd, J = 7.4, 2.2 Hz, 1H), 7.37 (ddd, J = 8.5, 4.7,2.2 Hz, 1H), 7.15- 7.04 (m, 3H), 7.00 (dd, J = 11.1, 1.6 Hz, 1H), 6.73(dt, J = 3.7, 1.0 Hz, 1H), 4.93 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.07(s, 2H), − 63 3.21 (d, J = 6.8 Hz, 2H), 2.49 (d, J = 1.1 Hz, 3H), 1.41(t, J = 7.1 Hz, 3H), 1.19- 1.06 (m, 1H), 0.49- 0.38 (m, 2H), 0.28 (dt, J= 6.1, 4.7 Hz, 2H); MS (M + H)⁺ = 655 230

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylfuran-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.29 (s,1H), 7.76 (dd, J = 7.4, 2.3 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.57 (s,2H), 7.54 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H), 7.33 (dd, J = 11.2, 8.6 Hz,1H), 7.20 (dd, J = 11.3, 1.6 Hz, 1H), 7.07 (dd, J = 8.1, 1.6 Hz, 1H),6.70 (t, J = +++ 64 3.5 Hz, 1H), 6.22 (dt, J = 3.1, 1.0 Hz, 1H), 4.15(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.17-1.06 (m, 1H),0.38-0.28 (m, 2H), 0.24-0.14 (m, 2H); MS (M + H)⁺ = 611 231

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiazol-2-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, TFA ¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.30(dd, J = 7.2, 2.3 Hz, 1H), 8.28 (s, 1H), 7.70-7.59 (m, 3H), 7.54 (s,2H), 7.43 (dd, J = 11.1, 8.7 Hz, 1H), 7.16 (dd, J = 11.4, 1.6 Hz, 1H),7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.14 (s, 2H), 3.19-3.14 (m, 2H), +++ 652.49 (d, J = 1.2 Hz, 3H), 1.18-1.05 (m, 1H), 0.39-0.29 (m, 2H),0.24-0.15 (m, 2H); MS (M + H)⁺ = 628 232

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(2- methylthiazol-5-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s,1H), 7.97 (s, 1H), 7.68 (dd, J = 7.4, 2.0 Hz, 1H), 7.64 (d, J = 7.9 Hz,1H), 7.57 (m, 3H), 7.39 (dd, J = 10.8, 8.7 Hz, 1H), 7.17 (d, J = 11.3Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.15 (s, 2H), 3.16 (d, J = 6.9 Hz,2H), 2.66 (s, +++ 66 3H), 1.18-1.01 (m, 1H), 0.37-0.27 (m, 2H), 0.21 (d,J = 4.9 Hz, 2H); MS (M + H)⁺ = 628 233

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(5- methylthiophen-2-yl)phenyl)-4-(2- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.29 (s,1H), 7.63 (dd, J = 7.5, 2.2 Hz, 1H), 7.56 (dd, J = 9.6, 1.8 Hz, 1H),7.53- 7.49 (m, 1H), 7.49- 7.44 (m, 1H), 7.42 (s, 2H), 7.34 (dd, J =11.3, 8.6 Hz, 1H), 7.19-7.11 (m, 2H), 6.81 (dt, J = 3.6, 1.1 Hz, 1H),4.08 (s, 2H), +++ 67 3.16 (d, J = 6.9 Hz, 2H), 2.44 (d, J = 1.1 Hz, 3H),1.17-1.02 (m, 1H), 0.35-0.27 (m, 2H), 0.22-0.14 (m, 2H); MS (M + H)⁺ =627 234

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (thiophen-2- yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole- 4-carboxylic acid,TFA; MS (M + H)⁺ = 613 +++ 68 235

¹H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 0.8 Hz, 1H), 7.74- 7.68 (m,2H), 7.67- 7.63 (m, 2H), 7.62 (s, 1H), 7.47-7.41 (m, 2H), 7.41-7.37 (m,2H), 7.26 (s, 2H), 4.13 (s, 2H); (M + H)⁺ = 476.4 + 161 236

(M + H)⁺ = 619.7 − 141 237

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.71-7.64 (m,2H), 7.63-7.55 (m, 2H), 7.37-7.23 (m, 6H), 6.99 (dt, J = 2.9, 1.6 Hz,1H), 6.95 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.89 (dtd, J = 7.6, 1.6, 0.9Hz, 1H), 4.14 (s, 2H), 3.75 (s, 3H), 3.13 (d, J = 6.9 Hz, 2H), 1.17-1.04(m, 1H), 0.36-0.27 (m, 2H), 0.22-0.15 (m, 2H); (M + H)⁺ = 619.7 +++ 141238

(M + H)⁺ = 607.7 + 141 239

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.73-7.68 (m,2H), 7.68-7.64 (m, 1H), 7.62 (dd, J = 7.6, 2.3 Hz, 1H), 7.54-7.46 (m,1H), 7.39 (dd, J = 10.8, 8.6 Hz, 1H), 7.35 (dd, J = 2.7, 1.4 Hz, 0H),7.34-7.27 (m, 5H), 7.26-7.22 (m, 1H), 7.18 (dq, J = 7.8, 1.3 Hz, 1H),4.18 (s, 2H), 3.17 (d, J = 6.9 Hz, 2H), 1.14 (ddd, J = 12.8, 7.7, 4.9Hz, 0H), 0.45- +++ 141 0.27 (m, 2H), 0.28- 0.14 (m, 2H); (M + H)⁺ =607.7 240

¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.46 (s, 1H), 7.80-7.72 (m,2H), 7.59 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.56 (dd, J = 7.5, 2.3 Hz,1H), 7.50-7.43 (m, 3H), 7.36-7.25 (m, 6H), 4.27 (s, 2H); (M + H)⁺ =621.6 +++ 14 241

¹H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.44 (s, 1H), 7.75-7.69 (m,2H), 7.62 (dd, J = 7.5, 2.3 Hz, 1H), 7.58 (ddd, J = 8.5, 4.8, 2.3 Hz,1H), 7.51-7.42 (m, 2H), 7.39-7.33 (m, 1H), 7.32-7.26 (m, 4H), 7.27-7.20(m, 2H), 4.25 (s, 2H); (M + H)⁺ = 621.6 +++ 14 242

¹H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.45 (s, 1H), 7.78-7.72 (m,2H), 7.63 (dd, J = 7.5, 2.3 Hz, 1H), 7.58 (ddd, J = 8.5, 4.7, 2.3 Hz,1H), 7.46 (dd, J = 10.6, 8.5 Hz, 1H), 7.40-7.29 (m, 6H), 7.04 (q, J =1.8 Hz, 1H), 7.01-6.95 (m, 2H), 4.27 (s, 2H), 3.76 (s, 3H); (M + H)⁺ =633.6 +++ 14 243

¹H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.42 (s, 1H), 7.77-7.70 (m,2H), 7.56-7.50 (m, 2H), 7.41 (dd, J = 10.7, 9.1 Hz, 1H), 7.33-7.26 (m,6H), 7.23 (dd, J- 8.4, 0.8 Hz, 2H), 4.23 (s, 2H), 2.31 (s, 3H); (M + H)⁺= 617.6 +++ 14 244

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.8 Hz, 1H), 7.66 (dt, J = 6.7,2.1 Hz, 1H), 7.59 (q, J = 1.6 Hz, 2H), 7.55 (dd, J = 10.9, 1.8 Hz, 1H),7.53-7.46 (m, 2H), 7.45-7.36 (m, 6H), 7.33 (ddd, J = 6.7, 4.9, 2.8 Hz,1H), 7.21 (t, J = 7.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H),2.17 (tt, J = 8.6, 5.6 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.97 (dt, J =11.2,3.2 Hz, 2H), − 112 0.73-0.58 (m, 2H); (M + H)⁺ = 603.7 245

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.3 Hz, 1H), 7.67 (t, J = 7.9Hz, 1H), 7.58 (s, 2H), 7.54 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.44 (dd, J= 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.5 Hz, 1H), 7.23 (d, J = 0.7Hz, 4H), 7.23-7.17 (m, 1H), 7.05 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 4.16 (s, 2H), 2.31 (s, 3H), 2.19 (tt, J = 8.6, 5.6 Hz, 1H),1.29 (t, J = 7.1 Hz, 3H), 1.03- 0.91 (m, 2H), 0.70- + 112 0.60 (m, 2H);(M + H)⁺ = 635.7 246

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 0.4 Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.60-7.43 (m, 5H), 7.38 (dd, J = 10.7, 8.5 Hz, 1H), 7.34-7.27(m, 1H), 7.27-7.13 (m, 3H), 7.06 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J =7.1 Hz, 2H), 4.17 (s, 2H), 2.26- 2.09 (m, 1H), 1.35- 1.22 (m, 3H), 1.03-0.90 (m, 2H), 0.65 (td, J = 6.1, 4.4 Hz, 2H); (M + H)⁺ = 639.7 + 112 247

¹H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.70 (t, J = 7.9 Hz, 1H),7.64-7.55 (m, 3H), 7.47 (dd, J = 7.6, 2.3 Hz, 1H), 7.44- 7.35 (m, 3H),7.28 (t, J = 8.9 Hz, 2H), 7.22 (d, J = 11.2 Hz, 1H), 7.08 (dd, J = 8.1,1.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 2.22 (tt, J = 8.5,5.7 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.08- 0.92 (m, 2H), 0.73- 0.64(m, 2H); (M + H)⁺ = 639.7 + 112 248

¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 0.5 Hz, 1H), 7.69 (t, J = 7.9Hz, 1H), 7.62-7.50 (m, 4H), 7.42-7.33 (m, 2H), 7.24-7.16 (m, 1H), 7.09(dd, J = 8.2, 1.6 Hz, 1H), 7.03-6.96 (m, 2H), 6.92 (dt, J = 7.7, 1.4 Hz,1H), 4.32 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 3.78 (s, 3H), 3.17 (dd, J =5.2, 0.5 Hz, 1H), 2.21 (tt, J = 8.5, 5.6 Hz, 1H), 1.36-1.27 (m, 3H),1.06-0.95 (m, 2H), 0.67 (td, J = 6.2, 4.4 − 112 Hz, 2H); (M + H)⁺ =651.7 249

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.28 (s, 1H), 7.67 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.53 (ddd, J = 8.5, 4.8, 2.3 Hz, 1H), 7.44(dd, J = 7.7, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.6 Hz, 1H), 7.23 (s,4H), 7.20 (dd, J = 11.3, 1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H),4.15 (s, 2H), 3.14 (d, J = 3.9 Hz, 1H), 2.31 (s, 3H), 2.23 (tt, J = 8.6,5.6 Hz, 1H), 1.01-0.89 (m, 2H), 0.68-0.59 +++ 112 (m, 2H); (M + H)⁺ =607.7 250

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.29 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.61-7.54 (m, 3H), 7.52 (dd, J = 7.5, 2.3 Hz, 1H), 7.47(td, J = 8.0, 6.1 Hz, 1H), 7.37 (dd, J = 10.7, 8.5 Hz, 1H), 7.31 (dd, J= 10.2, 2.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.20 (s, 0H), 7.05 (dd, J = 8.0,1.5 Hz, 1H), 4.17 (s, 2H), 2.23 (tt, J = 8.5, 5.5 Hz, 1H), 1.03-0.90 (m,2H), +++ 112 0.68-0.52 (m, 2H); (M + H)⁺ = 611.6 251

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.31 (s, 1H), 7.68 (t, J =7.9 Hz, 1H), 7.64-7.57 (m, 3H), 7.55 (dd, J = 7.6, 2.3 Hz, 1H), 7.50(td, J = 8.1, 6.2 Hz, 1H), 7.40 (dd, J = 10.7, 8.5 Hz, 1H), 7.34 (d, J =10.2 Hz, 1H), 7.29- 7.23 (m, 1H), 7.23 (s, 0H), 7.08 (dd, J = 8.0, 1.6Hz, 1H), 4.20 (s, 2H), 2.38-2.17 (m, 1H), 1.08-0.86 (m, 2H), 0.76-0.52(m, 2H); (M + H)⁺ = 611.6 +++ 112 252

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.30 (s, 1H), 7.69 (t, J =7.9 Hz, 1H), 7.58 (d, J = 4.8 Hz, 2H), 7.56-7.52 (m, 1H), 7.41-7.34 (m,2H), 7.24-7.17 (m, 1H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 7.02- 6.99 (m,1H), 6.98 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.92 (dd, J = 7.7, 1.3 Hz,1H), 4.19 (s, 2H), 3.78 (s, 3H), 2.34-2.13 (m, 1H), 1.10-0.93 (m, 2H),0.71-0.61 (m, 2H); (M + H)⁺ = 623.7 +++ 112 253

¹H NMR (400 MHz, DMSO-d6) δ 7.59- 7.44 (m, 3H), 7.42 (s, 2H), 7.33 (dd,J = 10.7, 8.5 Hz, 1H), 7.24 (d, J = 1.6 Hz, 3H), 7.17 (t, J = 7.8 Hz,1H), 4.10 (s, 2H), 2.34-2.27 (m, 3H), 2.19 (s, 0H), 0.95 (d, J = 9.0 Hz,2H), 0.62 (d, J = 5.6 Hz, 2H); (M + H)⁺ = 607.7 +++ 112 254

(M + H)⁺ = 611.6 +++ 112 255

¹H NMR (400 MHz, DMSO-d6) δ 7.62- 7.44 (m, 4H), 7.44- 7.27 (m, 3H),7.28- 7.11 (m, 3H), 4.11 (s, 2H), 2.18 (s, 0H), 0.96 (d, J = 8.1 Hz,2H), 0.62 (d, J = 5.6 Hz, 2H); (M + H)⁺ = 611.6 +++ 112 256

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.30 (s, 1H), 7.60-7.46 (m,4H), 7.40 (s, 2H), 7.40- 7.29 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.05-6.83 (m, 3H), 4.11 (s, 2H), 3.75 (s, 3H), 2.18 (tt, J = 8.5, 5.6 Hz,1H), 1.03-0.89 (m, 2H), 0.68-0.55 (m, 2H); (M + H)⁺ = 623.7 +++ 112 257

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.72 (d, J =8.2 Hz, 2H), 7.64 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 7.57 (dd, J = 7.6,2.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.42-7.34 (m, 4H), 7.32 (d, J = 9.4 Hz,4H), 4.17 (s, 2H), 3.17 (d, J = 6.9 Hz, 2H), 1.14 (h, J = 5.9, 5.3 Hz,1H), 0.33 (dt, J = 8.3,2.8 Hz, 2H), 0.28-0.15 (m, 2H); (M + H)⁺ = 589.7+++ 112 258

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.60- 7.49 (m, 4H), 7.35- 7.23 (m, 1H), 7.14(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 4.13 (s,2H), 3.15 (d, J = 6.8 Hz, 2H), 2.87 (p, J = 7.3 Hz, 1H), 2.05- 1.86 (m,2H), 1.69 (tdd, J = 9.3, 5.2, 2.7 Hz, 1H), 1.58 (dddd, J = 11.9, 10.4,6.0, 2.9 Hz, 3H), 1.11 (pd, J = 7.7, 3.7 Hz, 1H), 0.39- 0.29 (m, 2H),0.21 (dd, J = 5.0, 1.6 Hz, 2H); (M + H)⁺ = 623.7 +++ 145 259

¹H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.73-7.53 (m, 3H), 7.49 (ddd,J = 8.5, 4.8, 2.3 Hz, 1H), 7.37-7.09 (m, 3H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 5.93-5.74 (m, 1H), 4.11 (s, 2H), 3.21-3.05 (m, 4H), 2.62 (t, J =5.7 Hz, 2H), 2.31 (d, J = 13.8 Hz, 5H), 1.11 (dd, J = 9.3, 3.9 Hz, 1H),0.31 (dt, J = 8.2, 2.8 Hz, 2H), 0.27-0.12 (m, 2H); (M + H)⁺ = 626.7 +++145 260

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.76 (dd, J = 7.3,2.2 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.57-7.49 (m, 3H), 7.30 (dd, J =9.8, 8.6 Hz, 1H), 7.14- 7.07 (m, 1H), 7.06- 6.99 (m, 1H), 4.37- 4.24 (m,2H), 4.16 (s, 2H), 4.08 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.31 (td, J =7.1, 0.8 Hz, 3H), 1.18- 1.05 (m, 1H), 0.33 (dt, J = 8.2, 2.8 Hz, 2H),0.27-0.19 (m, + 145 2H); (M + H)⁺ = 599 261

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.15 (s, 1H), 7.64 (td, J =7.9, 3.0 Hz, 2H), 7.61-7.53 (m, 5H), 7.50 (dd, J = 6.9, 2.2 Hz, 1H),7.44 (ddd, J = 8.6, 5.1, 2.3 Hz, 1H), 7.31 (td, J = 9.0, 3.6 Hz, 2H),7.16- 6.98 (m, 4H), 4.13 (s, 2H), 3.80 (s, 2H), 3.25-3.12 (m, 6H), 3.02(qd, J = 8.8, 3.4 Hz, 6H), 2.42 (d, J = 6.8 Hz, 2H), 2.11- 1.93 (m, 4H),1.75 (ddq, J = 13.6, 9.1, 4.3 Hz, 4H), 1.19- 1.04 (m, 1H), 1.00- 0.85(m, 1H), 0.43- 0.37 (m, 2H), 0.36- 0.30 (m, 2H), 0.24- 0.18 (m, 2H),0.14- 0.08 (m, 2H); (M + H)⁺ = 639 +++ 145 262

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.56-7.47 (m, 2H), 7.27 (t, J = 9.0 Hz, 1H),7.13 (dd, J = 11.2, 1.5 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H), 4.12(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.57 (tt, J = 8.3, 5.0 Hz, 1H), 1.11(ddd, J = 13.1, 9.1, 5.9 Hz, 1H), 0.95- 0.86 (m, 2H), 0.78- 0.70 (m,2H), 0.37- 0.27 (m, 2H), 0.25- 0.16 (m, 2H); (M + H)⁺ = 597 +++ 145 263

¹H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.16 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.55-7.46 (m, 1H), 7.36 (t, J = 9.0 Hz, 1H),7.12-6.99 (m, 2H), 3.81 (s, 2H), 3.63 (s, 8H), 2.41 (d, J = 6.8 Hz, 2H),0.99- 0.86 (m, 1H), 0.45- 0.35 (m, 2H), 0.16- 0.05 (m, 2H); (M + H)⁺ =654.7 +++ 145 264

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.28 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.54 (dd, J = 7.3, 1.9 Hz, 1H), 7.52-7.48 (m,1H), 7.27 (t, J = 9.0 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02(dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.15 (d, J = 6.8 Hz, 2H), 1.57(tt, J = 8.3, 5.0 Hz, 1H), 1.11 (ddd, J = 12.8, 7.9, 5.4 Hz, 1H), 0.98-0.84 (m, 2H), 0.79- 0.67 (m, 2H), 0.32 +++ 145 (dt, J = 8.2, 2.8 Hz,2H), 0.23-0.14 (m, 2H); (M + H)⁺ = 595.6 265

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.59-7.52 (m, 4H), 7.30 (t, J = 9.4 Hz, 1H), 7.14 (dd, J =11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 5.53 (s, 1H), 4.14(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.45 (s, 6H), 1.20-1.05 (m, 1H),0.37-0.27 (m, 2H), 0.26-0.12 (m, 2H); (M + H)⁺ = 613.7 +++ 145 266

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.5 Hz, 1H), 7.71- 7.52 (m,6H), 7.47 (td, J = 7.6, 2.2 Hz, 1H), 7.34 (dd, J = 8.2, 2.3 Hz, 2H),7.27- 7.16 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 4.30 (qd, J = 7.1, 2.3 Hz,2H), 4.17 (s, 2H), 3.21-3.08 (m, 2H), 2.30 (d, J = 2.1 Hz, 3H), 1.30(td, J = 7.1, 2.3 Hz, 3H), 1.15 (ddd, J = 9.8, 5.2, 2.0 Hz, 1H), 0.32(td, J = + 145 5.8, 5.4, 2.7 Hz, 2H), 0.24 (d, J = 4.9 Hz, 2H); (M + H)⁺= 631.8 267

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.59(s, 2H), 7.26 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 11.4, 1.6 Hz, 1H), 7.04(ddd, J = 14.9, 7.5, 1.5 Hz, 2H), 6.95 (dd, J = 8.3, 2.5 Hz, 1H), 6.81(t, J = 2.0 Hz, 1H), 4.10 (s, 2H), 3.72-3.60 (m, 4H), 3.15 (d, J = 6.9Hz, 2H), 2.95-2.83 (m, 4H), 1.12 (dtt, J = 14.8, 7.2, 3.7 Hz, 1H),0.37-0.27 (m, 2H), +++ 145 0.24-0.17 (m, 2H); (M + H)⁺ = 598.7 268

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.64 (t, J = 7.9Hz, 1H), 7.59-7.49 (m, 4H), 7.31-7.23 (m, 1H), 7.14 (dd, J = 11.3, 1.6Hz, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H), 4.30 (qd, J = 7.1, 0.8 Hz, 2H),4.13 (s, 2H), 3.15 (d, J = 6.8 Hz, 2H), 2.87 (p, J = 7.2 Hz, 1H),2.05-1.90 (m, 2H), 1.79-1.66 (m, 1H), 1.64-1.50 (m, 4H), 1.31 (td, J =7.1, 0.7 Hz, 3H), 1.18- 1.02 (m, 2H), 0.33 (dt, J = 8.1, 2.8 Hz, 2H),0.28-0.17 (m, 2H); (M + H)⁺ = 651.8 − 145 269

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 0.7 Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 7.53 (d, J = 6.7 Hz, 3H), 7.51-7.44 (m, 0H), 7.41-7.30 (m, 2H),7.12 (d, J = 11.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 4.30 (q, J = 7.1Hz, 2H), 4.13 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.02 (s, 3H), 1.41-1.22(m, 3H), 1.12 (s, 2H), 0.43- 0.29 (m, 2H), 0.23 (q, J = 4.9 Hz, 2H);(M + H)⁺ = 579.7 + 145 270

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.59-7.50 (m, 3H), 7.50-7.44 (m, 1H), 7.39-7.30 (m, 2H),7.12 (dd, J = 11.5, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13(s, 2H), 3.19-3.07 (m, 3H), 2.02 (s, 3H), 1.19- 0.97 (m, 1H), 0.38- 0.27(m, 2H), 0.27- 0.10 (m, 2H); (M + H)⁺ = 551.6 +++ 145 271

(M + H)⁺ = 465 + 16 272

(M + H)⁺ = 509 − 112 273

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.74-7.64 (m, 2H), 7.45-7.35(m, 2H), 7.34-7.27 (m, 3H), 7.22 (s, 2H), 7.14-7.07 (m, 2H), 4.15 (q, J= 7.1 Hz, 2H), 2.55-2.49 (m, 1H), 1.94-1.39 (m, 7H), 1.26-1.11 (m, 6H);(M + H)⁺ = 553 − 33 274

¹H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78-7.68 (m, 4H), 7.42-7.26(m, 3H), 7.22 (s, 2H), 7.18-7.09 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.88(tt, J = 12.0, 3.1 Hz, 1H), 1.96- 1.44 (m, 7H), 1.39- 0.98 (m, 6H); (M +H)⁺ = 553 − 33 275

(M + H)⁺ = 531 + 112 276

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.75-7.64 (m,4H), 7.59 (dt, J = 7.7, 1.3 Hz, 1H), 7.52-7.46 (m, 1H), 7.45-7.37 (m,4H), 7.37-7.30 (m, 3H), 7.28 (s, 2H), 4.16 (s, 2H), 3.16 (m, 2H), 1.13(ddtd, J = 13.0, 8.0, 6.9, 4.9 Hz, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m,2H); (M + H)⁺ = 571 +++ 141 277

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.79-7.61 (m,2H), 7.37-7.09 (m, 6H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 3.84 (s,2H), 3.71 (s, 3H), 2.40 (d, J = 6.8 Hz, 2H), 0.99-0.82 (m, 1H),0.43-0.33 (m, 2H), 0.13-0.05 (m, 2H); (M + H)⁺ = 543 + 141 278

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.79-7.61 (m,2H), 7.37-7.09 (m, 6H), 6.89 (ddd, J = 8.3, 4.3, 2.0 Hz, 1H), 3.84 (s,2H), 3.71 (s, 3H), 2.40 (d, J = 6.8 Hz, 2H), 0.99-0.82 (m, 1H),0.43-0.33 (m, 2H), 0.13-0.05 (m, 2H); (M + H)⁺ = 543 +++ 141 279

(M + H)⁺ = 599 + 141 280

(M + H)⁺ = 585 + 141 281

(M + H)⁺ = 585 +++ 141 282

(M + H)⁺ = 603 +++ 141 283

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.70-7.63 (m,2H), 7.52 (dd, J = 7.6, 2.2 Hz, 1H), 7.40-7.15 (m, 11H), 3.85 (s, 2H),2.39 (d, J = 6.8 Hz, 2H), 2.29 (s, 3H), 0.91 (dddd, J = 11.6, 8.1, 5.0,2.0 Hz, 1H), 0.42-0.33 (m, 2H), 0.13-0.04 (m, 2H); (M + H)⁺ = 603 + 141284

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.26 (s, 1H), 7.72-7.66 (m,2H), 7.61-7.48 (m, 2H), 7.35-7.19 (m, 10H), 4.13 (s, 2H), 3.14 (d, J =6.9 Hz, 2H), 2.31 (s, 3H), 1.17-1.05 (m, 1H), 0.33-0.26 (m, 2H),0.22-0.15 (m, 2H); (M + H)⁺ = 603 +++ 141 285

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.16 (s, 1H), 7.55-7.44 (m,3H), 7.39 (s, 2H), 7.39- 7.13 (m, 8H), 3.83 (s, 2H), 2.43 (d, J = 6.8Hz, 2H), 2.30 (s, 3H), 0.98-0.86 (m, 1H), 0.43-0.33 (m, 2H), 0.15-0.06(m, 2H); (M + H)⁺ = 621 + 145 286

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.18 (s, 1H), 7.68-7.57 (m,3H), 7.55 (s, 2H), 7.48- 7.38 (m, 3H), 7.30 (ddd, J = 7.6, 1.8, 1.1 Hz,1H), 7.22-7.15 (m, 2H), 7.09 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J =8.1, 1.6 Hz, 1H), 3.86 (s, 2H), 2.42 (d, J = 6.8 Hz, 2H), 2.28 (s, 3H),1.00-0.87 (m, 1H), 0.44-0.34 (m, 2H), 0.15-0.06 (m, 2H); (M + H)⁺ =603 + 145 287

¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.17 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.58-7.47 (m, 1H), 7.40-7.24 (m, 5H),7.24-7.17 (m, 2H), 7.22-7.06 (m, 2H), 7.09-6.97 (m, 1H), 3.86 (s, 2H),2.41 (d, J = 6.8 Hz, 2H), 2.30 (s, 3H), 0.92 (dddd, J = 11.6, 8.1,5.0,1.9 Hz, 1H), 0.43-0.34 (m, 2H), 0.14-0.06 (m, 2H); (M + H)⁺ = 621 + 145288

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.24 (s, 1H), 7.69-7.53 (m,2H), 7.57 (s, 2H), 7.49 (dd, J = 7.6, 2.3 Hz, 1H), 7.32 (dd, J = 10.7,8.5 Hz, 1H), 7.24 (s, 3H), 7.26-7.12 (m, 2H), 7.04 (dd, J = 8.1, 1.6 Hz,1H), 4.14 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.31 (s, 3H), 1.18-1.00 (m,1H), 0.36-0.25 (m, 2H), 0.23-0.15 (m, 2H); (M + H)⁺ = 621 +++ 145 289

(M + H)⁺ = 589 + 145 290

(M + H)⁺ = 589 +++ 145 291

¹H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.18 (s, 1H), 7.71-7.57 (m,3H), 7.57-7.49 (m, 4H), 7.46 (td, J = 7.7, 0.6 Hz, 1H), 7.43-7.34 (m,2H), 7.37-7.26 (m, 2H), 7.13-6.99 (m, 2H), 3.87 (s, 2H), 2.43 (d, J =6.8 Hz, 2H), 1.02-0.86 (m, 1H), 0.44-0.34 (m, 2H), 0.15-0.07 (m, 2H);(M + H)⁺ = 589 + 145 292

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.16 (s, 1H), 7.70-7.63 (m,2H), 7.68-7.43 (m, 3H), 7.42-7.27 (m, 2H), 7.28-7.17 (m, 6H), 3.85 (s,2H), 2.39 (d, J = 6.8 Hz, 2H), 0.92 (dddd, J = 13.3, 8.1, 5.0, 2.0 Hz,1H), 0.42- 0.33 (m, 2H), 0.13- 0.04 (m, 2H); (M + H)⁺ = 607 + 145 293

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.16 (s, 1H), 7.72-7.63 (m,2H), 7.50 (dd, J = 7.6, 2.2 Hz, 1H), 7.40-7.26 (m, 4H), 7.29-7.20 (m,4H), 7.12-7.04 (m, 2H), 3.85 (s, 2H), 2.39 (d, J = 6.8 Hz, 2H), 1.90(tt, J = 8.3, 5.1 Hz, 1H), 0.98- 0.88 (m, 3H), 0.73- 0.62 (m, 2H), 0.42-0.31 (m, 2H), 0.15- 0.04 (m, 2H); (M + H)⁺ = 629 + 145 294

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.77-7.64 (m,2H), 7.60 (ddd, J = 8.5, 4.7, 2.3 Hz, 1H), 7.52 (dd, J = 7.7, 2.3 Hz,1H), 7.41-7.28 (m, 4H), 7.31-7.18 (m, 2H), 7.18-7.08 (m, 2H), 4.16 (s,2H), 3.21-3.14 (m, 2H), 1.94 (tt, J = 8.3, 5.0 Hz, 1H), 1.21-1.07 (m,1H), 1.05-0.92 (m, 2H), 0.79-0.65 (m, 2H), 0.38-0.30 (m, 2H), 0.25-0.18+++ 145 (m, 2H); (M + H)⁺ = 629 295

(M + H)⁺ = 592 + 141 296

(M + H)⁺ = 592 +++ 141 297

¹H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.76-7.70 (m, 2H), 7.69-7.62(m, 3H), 7.48 (td, J = 7.6, 0.7 Hz, 1H), 7.45- 7.31 (m, 8H), 7.30 (s,2H), 4.40-4.35 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz,7H); (M + H)⁺ = 653 − 49 298

¹H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 7.68-7.58 (m, 4H), 7.49-7.43(m, 2H), 7.44-7.33 (m, 3H), 7.34-7.27 (m, 2H), 7.25-7.18 (m, 4H), 3.99(s, 2H), 1.37-1.24 (m, 2H), 1.04 (s, 2H); (M + H)⁺ = 653 + 49 299

¹H NMR (400 MHz, DMSO-d) δ 13.07 (s, 1H), 8.31 (s, 1H), 7.73-7.65 (m,2H), 7.70-7.57 (m, 3H), 7.49-7.40 (m, 1H), 7.43-7.24 (m, 10H), 4.33 (s,2H), 1.81- 0.93 (m, 4H); (M + H)⁺ = 625 + 49 300

¹H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.31 (s, 1H), 7.68-7.48 (m,4H), 7.50-7.36 (m, 8H), 7.39-7.28 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H),4.27 (s, 2H), 1.73-1.10 (m, 4H); (M + H)⁺ = 643 ++ 49 301

(M + H)⁺ = 643 + 49 302

¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.30 (s, 1H), 7.67-7.54 (m,6H), 7.50-7.40 (m, 1H), 7.44-7.34 (m, 4H), 7.39-7.27 (m, 1H), 7.19 (dd,J = 11.4, 1.6 Hz, 1H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.34 (s, 2H),1.81-0.93 (m, 4H); (M + H)⁺ = 643 + 49 303

¹H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.23 (s, 1H), 7.72-7.56 (m,4H), 7.54-7.28 (m, 7H), 7.32-7.16 (m, 4H), 3.93 (s, 2H), 3.70 (q, J =11.2 Hz, 2H); (M + H)⁺ = 599 + 49 304

¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.30 (s, 1H), 7.72-7.57 (m,5H), 7.47 (td, J = 7.7, 0.6 Hz, 1H), 7.45-7.23 (m, 9H), 4.66 (q, J =10.5 Hz, 2H), 4.26 (s, 2H); (M + H)⁺ = 599 ++ 49 305

¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.71-7.63 (m, 2H), 7.53 (dd,J = 7.6, 2.2 Hz, 1H), 7.40- 7.26 (m, 4H), 7.29- 7.21 (m, 6H), 3.85 (s,2H), 2.88 (hept, J = 6.9 Hz, 1H), 2.39 (d, J = 6.8 Hz, 2H), 1.19 (s,sH), 1.18 (s, 3H), 0.92 (dddd, J = 11.8, 6.8, 5.6, 2.9 Hz, 1H), 0.44-0.31 (m, 2H), 0.15- 0.04 (m, 2H); (M + H)⁺ = 631 + 145 306

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.73-7.66 (m,2H), 7.61-7.46 (m, 2H), 7.38-7.20 (m, 10H), 4.13 (s, 2H), 3.14 (d, J =6.9 Hz, 2H), 2.89 (hept, J = 6.9 Hz, 1H), 1.21 (s, 3H), 1.19 (s, 3H),1.15-1.04 (m, 1H), 0.35-0.26 (m, 2H), 0.23-0.14 (m, 2H); (M + H)⁺ = 631+++ 145 307

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.59-7.44 (m,4H), 7.42 (s, 2H), 7.32 (dd, J = 10.8, 8.5 Hz, 1H), 7.24 (s, 1H), 7.24(s, 3H), 7.14 (t, J = 7.8 Hz, 1H), 4.09 (s, 2H), 3.15 (d, J = 6.9 Hz,2H), 2.50 (s, 1H), 2.31 (s, 3H), 1.15- 1.02 (m, 1H), 0.35- 0.14 (m, 4H);(M + H)⁺ = 621 +++ 145 308

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.17 (s, 1H), 7.60-7.41 (m,5H), 7.44-7.14 (m, 7H), 3.84 (s, 2H), 2.52- 2.51 (m, 2H), 0.99- 0.84 (m,1H), 0.43- 0.34 (m, 2H), 0.15- 0.06 (m, 2H); (M + H)⁺ = 625 + 145 309

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.62-7.49 (m,2H), 7.49 (ddd, J = 8.4, 6.3, 2.1 Hz, 2H), 7.42 (s, 2H), 7.39 (ddd, J =8.9, 5.4, 1.4 Hz, 2H), 7.34 (dd, J = 10.7, 8.6 Hz, 1H), 7.31-7.21 (m,2H), 7.14 (t, J = 7.8 Hz, 1H), 4.09 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),1.15-1.02 (m, 1H), 0.35-0.26 (m, 2H), 0.29-0.15 (m, 2H); (M + H)⁺ = 625+++ 145 310

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.26 (s, 1H), 7.73-7.65 (m,2H), 7.62 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 7.49 (dd, J = 7.6, 2.3 Hz,1H), 7.41-7.29 (m, 3H), 7.32-7.19 (m, 6H), 4.13 (s, 2H), 3.15 (d, J =6.9 Hz, 2H), 2.50 (s, 1H), 1.19-1.02 (m, 1H), 0.35-0.24 (m, 2H),0.27-0.15 (m, 2H); (M + H)⁺ = 607 +++ 145 311

(M + H)⁺ = 599 +++ 14, 18 312

(M + H)⁺ = 603 +++ 14, 18 313

(M + H)⁺ = 603 +++ 14, 18 314

(M + H)⁺ = 615 +++ 14, 18 315

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.66 (dd, J = 7.6, 2.2 Hz,1H), 7.52- 7.36 (m, 5H), 7.40- 7.27 (m, 4H), 7.26- 7.16 (m, 2H), 4.10(q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 2.44 (d, J = 6.8 Hz, 2H), 1.10 (t, J= 7.1 Hz, 3H), 0.99- 0.86 (m, 1H), 0.44- 0.34 (m, 2H), 0.16- 0.07 (m,2H); (M + H)⁺ = 653 − 141 316

(M + H)⁺ = 653 + 141 317

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.69 (dd, J = 7.6, 2.2 Hz,1H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (s, 2H), 7.52-7.34 (m, 2H),7.38-7.31 (m, 1H), 7.35-7.27 (m, 2H), 7.21 (dddd, J = 9.0, 8.3, 2.6, 1.0Hz, 1H), 7.11 (dd, J = 11.4, 1.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz,1H), 4.10 (q, J = 7.1 Hz, 2H), 3.88 (s, − 141 2H), 2.41 (d, J = 6.8 Hz,2H), 1.10 (t, J = 7.1 Hz, 3H), 0.99- 0.87 (m, 1H), 0.44- 0.34 (m, 2H),0.15- 0.06 (m, 2H); (M + H)⁺ = 653 318

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.68-7.55 (m, 3H), 7.56 (s,2H), 7.48 (ddd, J = 8.4, 7.7, 6.2 Hz, 1H), 7.42- 7.29 (m, 2H), 7.34-7.16 (m, 2H), 7.21- 7.11 (m, 2H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.29(q, J = 7.1 Hz, 2H), 4.17 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.30 (t, J= 7.1 Hz, 3H), 1.25-0.96 (m, 1H), 0.37-0.19 (m, 4H); (M + H)⁺ = 653 −141 319

(M + H)⁺ = 665 − 141 320

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.61-7.44 (m, 4H), 7.43-7.29(m, 4H), 7.14 (t, J = 7.8 Hz, 1H), 7.02-6.94 (m, 1H), 6.99-6.87 (m, 1H),4.29 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.76 (s, 3H), 3.15 (d, J = 6.9Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.20-0.95 (m, 0H), 0.36-0.17 (m, 4H);(M + H)⁺ = 665 − 141 321

¹H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.67-7.58 (m, 2H), 7.55 (s,2H), 7.44-7.27 (m, 3H), 7.15-6.89 (m, 6H), 4.10 (q, J = 7.1 Hz, 2H),3.88 (s, 2H), 3.72 (s, 3H), 2.41 (d, J = 6.8 Hz, 2H), 1.11 (t, J = 7.1Hz, 3H), 1.01-0.78 (m, 1H), 0.43-0.34 (m, 2H), 0.15-0.06 (m, 2H); (M +H)⁺ = 665 − 141 322

(M + H)⁺ = 665 + 141 323

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.18 (s, 1H), 7.66 (dd, J =7.6, 2.2 Hz, 1H), 7.52-7.25 (m, 7H), 7.39 (s, 2H), 7.26-7.15 (m, 2H),3.85 (s, 2H), 2.44 (d, J = 6.8 Hz, 2H), 1.00- 0.85 (m, 1H), 0.44- 0.34(m, 2H), 0.15- 0.07 (m, 2H); (M + H)⁺ = 625 + 141 324

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.64-7.55 (m,2H), 7.55-7.43 (m, 3H), 7.43-7.09 (m, 7H), 4.11 (s, 2H), 3.16 (d, J =6.9 Hz, 2H), 1.21- 0.95 (m, 1H), 0.36- 0.25 (m, 2H), 0.28- 0.15 (m, 2H);(M + H)⁺ = 625 +++ 141 325

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.17 (s, 1H), 7.73-7.58 (m,2H), 7.55 (s, 2H), 7.50- 7.40 (m, 1H), 7.44- 7.33 (m, 2H), 7.37- 7.29(m, 2H), 7.21 (dddd J = 9.1, 8.3, 2.6, 1.0 Hz, 1H), 7.14- 6.99 (m, 2H),3.88 (s, 2H), 2.41 (d, J = 6.8 Hz, 2H), 1.00- 0.85 (m, 1H), 0.44- 0.34(m, 2H), 0.15- 0.06 (m, 2H); (M + H)⁺ = 625 + 141 326

(M + H)⁺ = 625 +++ 141 327

¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.18 (s, 1H), 7.57 (dd, J =7.6, 2.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.42-7.23 (m, 5H), 7.20 (t, J = 7.9Hz, 1H), 7.06- 6.97 (m, 2H), 6.92 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.85(s, 2H), 3.72 (s, 3H), 2.43 (d, J = 6.8 Hz, 2H), 1.06- 0.78 (m, 1H),0.43- 0.32 (m, 2H), 0.17- 0.04 (m, 2H); (M + H)⁺ = 637 + 141 328

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.61-7.44 (m,4H), 7.41 (s, 2H), 7.39- 7.29 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H), 7.0-26.87 (m, 3H), 4.11 (s, 2H), 3.76 (s, 3H), 3.15 (d, J = 6.9 Hz, 2H),1.20-0.98 (m, 1H), 0.35-0.26 (m, 2H), 0.29-0.15 (m, 2H); (M + H)⁺ = 637+++ 141 329

¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.17 (s, 1H), 7.67-7.57 (m,2H), 7.55 (s, 2H), 7.43- 7.26 (m, 3H), 7.15- 6.97 (m, 4H), 6.92 (ddd, J= 8.3, 2.6, 0.9 Hz, 1H), 3.88 (s, 2H), 3.72 (s, 3H), 2.40 (d, J = 6.8Hz, 2H), 0.92 (dddd, J = 14.8, 8.0, 5.0, 1.9 Hz, 1H), 0.43- 0.34 (m,2H), 0.14- 0.06 (m, 2H); (M + H)⁺ = 637 + 141 330

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.68-7.54 (m,3H), 7.56 (s, 2H), 7.39- 7.29 (m, 2H), 7.15 (dd, J = 11.3, 1.6 Hz, 1H),7.09-6.86 (m, 4H), 4.16 (s, 2H), 3.75 (s, 3H), 3.14 (d, J = 6.9 Hz, 2H),1.11 (s, 1H), 0.36-0.27 (m, 2H), 0.24-0.15 (m, 2H); (M + H)⁺ = 637 +++141 331

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.71-7.62 (m,2H), 7.66-7.53 (m, 2H), 7.58 (s, 2H), 7.56- 7.29 (m, 6H), 7.19 (dd, J =11.4, 1.6 Hz, 1H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 4.17 (s, 2H), 3.16(d, J = 6.9 Hz, 2H), 1.23-1.07 (m, 1H), 0.37-0.28 (m, 2H), 0.31-0.17 (m,2H); (M + H)⁺ = 589 +++ 141 332

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.71-7.53 (m,4H), 7.58 (s, 2H), 7.57- 7.40 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.26-7.15 (m, 3H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J =6.9 Hz, 2H), 2.30 (s, 3H), 1.23-1.01 (m, 1H), 0.37-0.28 (m, 2H),0.25-0.16 (m, 2H); (M + H)⁺ = 603 +++ 141 333

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.56(s, 2H), 7.32-7.23 (m, 1H), 7.14 (dd, J = 11.3, 1.5 Hz, 1H), 7.12-7.01(m, 2H), 6.94-6.83 (m, 2H), 4.58 (dq, J = 6.0, 3.0 Hz, 1H), 4.29 (q, J =7.1 Hz, 2H), 4.11 (s, 2H), 3.12 (d, J = 6.9 Hz, 2H), 1.80- 1.68 (m, 2H),1.68- 1.59 (m, 3H), 1.59- 1.47 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.16-1.04 (m, 1H), 0.36- + 120 0.27 (m, 2H), 0.27- 0.17 (m, 2H); (M + H)⁺ =625 334

¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.73-7.65 (m, 2H), 7.32-7.22(m, 5H), 7.09 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.95-6.83 (m, 2H), 4.54(dq, J = 6.1, 3.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 3.11(d, J = 6.9 Hz, 2H), 1.78-1.41 (m, 8H), 1.30 (t, J = 7.1 Hz, 3H), 1.14-1.10 m, 1H), 0.35- 0.25 (m, 2H), 0.25- 0.16 (m, 2H); − 141 (M + H)⁺ =607 335

¹H NMR (400 MHz, DMSO-d6) δ 8.49- 8.24 (m, 1H), 7.60- 7.45 (m, 2H), 7.41(s, 2H), 7.27 (ddd, J = 8.2, 7.7, 0.5 Hz, 1H), 7.18-7.02 (m, 2H),6.96-6.83 (m, 2H), 4.57 (dq, J = 5.9, 3.0 Hz, 1H), 4.29 (q, J = 7.1 Hz,2H), 4.06 (s, 2H), 3.13 (d, J = 7.0 Hz, 2H), 1.92-1.40 (m, 8H), 1.30 (t,J = 7.1 Hz, 3H), 1.23- 0.93 (m, 1H), 0.39- 0.26 (m, 2H), 0.24- 0.13 (m,2H); (M + H)⁺ = 625 + 120 336

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 0H), 8.27 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.18-7.07 (m, 2H),7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.94- 6.83 (m, 2H), 4.58 (tt, J = 5.7,2.5 Hz, 1H), 4.11 (s, 2H), 3.12 (d, J = 6.9 Hz, 2H), 1.78- 1.46 (m, 8H),1.23- 0.93 (m, 1H), 0.35- 0.14 (m, 4H); (M + H)⁺ = 597 +++ 120 337

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.27 (s, 1H), 7.72-7.65 (m,2H), 7.32-7.19 (m, 6H), 7.09 (ddd, J = 7.6, 1.6, 1.0 Hz, 1H), 6.95- 6.82(m, 3H), 4.54 (dq, J = 6.1, 3.1 Hz, 1H), 4.09 (s, 2H), 3.11 (d, J = 6.9Hz, 2H), 1.78-1.69 (m, 2H), 1.69-1.57 (m, 4H), 1.57-1.46 (m, 4H),1.21-0.93 (m, 1H), 0.34-0.25 (m, 2H), 0.22-0.13 (m, 2H); (M + H)⁺ = 579+++ 120 338

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.58-7.45 (m, 2H), 7.41 (s,2H), 7.27 (t, J = 7.9 Hz, 1H), 7.16-7.02 (m, 2H), 6.93-6.83 (m, 2H),4.56 (tt, J = 5.6, 2.5 Hz, 1H), 4.05 (s, 2H), 3.13 (d, J = 6.9 Hz, 2H),1.80-1.46 (m, 8H), 1.20-0.82 (m, 1H), 0.34-0.26 (m, 2H), 0.26-0.14 (m,2H); (M + H)⁺ = 597 +++ 120 339

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.72-7.64 (m,2H), 7.42-7.20 (m, 10H), 7.16-7.07 (m, 2H), 7.00 (ddd, J = 8.3, 2.6, 1.0Hz, 1H), 5.01 (s, 2H), 4.09 (s, 2H), 3.11 (d, J = 6.9 Hz, 2H), 1.09(ddtd, J = 13.0, 7.9, 6.9, 5.0 Hz, 1H), 0.35-0.25 (m, 2H), 0.22-0.13 (m,2H); (M + H)⁺ = 601 +++ 120 340

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.42-7.24 (m, 6H), 7.16-7.05 (m, 3H), 7.00(ddt, J = 8.3, 2.6, 1.2 Hz, 2H), 5.03 (s, 2H), 4.10 (s, 2H), 3.12 (d, J= 6.9 Hz, 2H), 1.14-0.98 (m, 1H), 0.35-0.24 (m, 2H), 0.25-0.14 (m, 2H);(M + H)⁺ = 619 +++ 120 341

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.58-7.43 (m,2H), 7.43-7.24 (m, 8H), 7.16-6.96 (m, 4H), 5.04 (s, 2H), 4.05 (s, 2H),3.12 (d, J = 6.9 Hz, 2H), 1.18-0.96 (m, 1H), 0.34-0.25 (m, 2H),0.22-0.13 (m, 2H); (M + H)⁺ = 619 +++ 120 342

¹H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.18 (s, 1H), 7.73-7.63 (m,2H), 7.50-7.05 (m, 12H), 7.03 (ddd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.90 (dt,J = 7.6, 1.1 Hz, 1H), 5.05 (s, 2H), 3.79 (s, 2H), 2.36 (d, J = 6.8 Hz,2H), 0.98- 0.83 (m, 1H), 0.43- 0.31 (m, 2H), 0.12- 0.03 (m, 2H); (M +H)⁺ = 601 + 120 343

¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.69-7.54 (m, 2H), 7.58 (s,2H), 7.50 (dd, J = 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7, 8.6 Hz, 1H),7.24 (s, 3H), 7.29- 7.13 (m, 2H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 4.29(q, J = 7.1 Hz, 2H), 4.15 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.32 (s,3H), 1.30 (t, J = 7.1 Hz, 3H), 1.21-1.00 (m, 1H), 0.37-0.26 (m, 2H),0.23 (dt, J = 5.1, + 141 2.6 Hz, 2H); (M + H)⁺ = 649 344

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.67-7.41 (m, 9H), 7.38-7.29(m, 2H), 7.26-7.13 (m, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.15(dd, J = 9.8, 6.1 Hz, 3H), 2.30 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H),1.25-0.96 (m, 0H), 0.37-0.19 (m, 4H); (M + H)⁺ = 631 − 145 345

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.63-7.45 (m, 4H), 7.43 (s,2H), 7.45-7.30 (m, 3H), 7.32-7.21 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H),4.29 (q, J = 7.1 Hz, 2H), 4.10 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.30(t, J = 7.1 Hz, 3H), 1.20-0.91 (m, 0H), 0.37-0.18 (m, 4H); (M + H)⁺ =653 + 145 346

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.15 (s, 1H), 7.70-7.54 (m,5H), 7.50-7.40 (m, 3H), 7.30 (dt, J = 7.7, 1.3 Hz, 1H), 7.24-7.08 (m,3H), 7.13-7.02 (m, 1H), 3.92 (s, 2H), 2.29 (s, 3H), 1.77 (tt, J = 7.5,5.6 Hz, 1H), 0.85 (ddd, J = 6.9, 3.5, 1.6 Hz, 4H); (M + H)⁺ = 589 + 112347

¹H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.31 (s, 1H), 7.73-7.41 (m,7H), 7.31 (d, J = 8.2 Hz, 2H), 7.26-7.17 (m, 3H), 7.08 (dd, J = 8.2, 1.6Hz, 1H), 4.16 (s, 2H), 2.30 (s, 3H), 2.30-2.19 (m, 1H), 1.02-0.92 (m,2H), 0.70-0.61 (m, 2H); (M + H)⁺ = 589 +++ 112 348

(M + H)⁺ = 593 + 112 349

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.74-7.60 (m,2H), 7.60 (s, 2H), 7.59- 7.39 (m, 5H), 7.27- 7.18 (m, 3H), 7.08 (dd, J =8.1, 1.6 Hz, 1H), 4.17 (s, 2H), 2.25 (tt, J = 8.5, 5.5 Hz, 1H),1.04-0.93 (m, 2H), 0.73-0.62 (m, 2H); (M + H)⁺ = 593 +++ 112 350

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.15 (s, 1H), 7.78-7.69 (m,2H), 7.64 (t, J = 7.9 Hz, 1H), 7.55 (s, 2H), 7.52-7.39 (m, 4H),7.43-7.32 (m, 1H), 7.20-7.02 (m, 3H), 3.93 (s, 2H), 1.76 (tt, J = 7.6,5.5 Hz, 1H), 0.90-0.78 (m, 4H); (M + H)⁺ = 593 + 112 351

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.74-7.61 (m,3H), 7.59-7.44 (m, 4H), 7.49-7.35 (m, 2H), 7.26-7.04 (m, 4H), 4.18 (s,2H), 2.24 (tt, J = 8.5, 5.6 Hz, 1H), 1.04-0.91 (m, 2H), 0.72-0.61 (m,2H); (M + H)⁺ = 593 +++ 112 352

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.15 (s, 1H), 7.73-7.60 (m,3H), 7.55 (s, 2H), 7.48 (td, J = 7.7, 0.5 Hz, 1H), 7.37-7.25 (m, 2H),7.17-7.03 (m, 4H), 6.88 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.93 (s, 2H),3.29 (s, 9H), 1.75 (tt, J = 7.5, 5.6 Hz, 1H), 0.90-0.78 (m, 4H); (M +H)⁺ = 605 + 112 353

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.30 (s, 1H), 7.72-7.59 (m,3H), 7.59-7.40 (m, 4H), 7.36-7.25 (m, 1H), 7.20 (dd, J = 11.3, 1.6 Hz,1H), 7.12-7.03 (m, 2H), 6.93 (dddd, J = 21.2, 8.3, 2.2, 0.9 Hz, 2H),4.17 (s, 2H), 3.76 (s, 3H), 2.24 (tt, J = 8.5, 5.6 Hz, 1H), 1.01-0.90(m, 2H), 0.71-0.58 (m, 2H); (M + H)⁺ = 605 +++ 112 354

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.16 (s, 1H), 7.69-7.49 (m,3H), 7.54-7.46 (m, 1H), 7.50-7.39 (m, 5H), 7.33-7.15 (m, 4H), 3.90 (s,2H), 2.29 (s, 3H), 1.76 (p, J = 6.8 Hz, 1H), 0.87-0.80 (m, 4H); (M +H) =589 + 112 355

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.31 (s, 1H), 7.69-7.49 (m,4H), 7.52-7.42 (m, 2H), 7.43 (s, 2H), 7.37- 7.28 (m, 2H), 7.25- 7.16 (m,3H), 4.11 (s, 2H), 2.30 (s, 3H), 2.21 (tt, J = 8.5, 5.6 Hz, 1H),1.02-0.92 (m, 2H), 0.69-0.60 (m, 2H); (M + H)+ = 589 +++ 112 356

(M + H)⁺ = 593 + 112 357

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.30 (s, 1H), 7.65 (dt, J =6.6, 2.1 Hz, 1H), 7.65-7.53 (m, 2H), 7.58-7.46 (m, 3H), 7.50-7.41 (m,4H), 7.29-7.16 (m, 3H), 4.11 (s, 2H), 2.21 (tt, J = 8.6, 5.6 Hz, 1H),1.02-0.91 (m, 2H), 0.71-0.60 (m, 2H); (M + H)⁺ = 593 +++ 112 358

¹H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.15 (s, 1H), 7.72 (ddd, J =9.7, 1.8, 0.9 Hz, 2H), 7.55- 7.46 (m, 1H), 7.50 (s, 1H), 7.51-7.38 (m,4H), 7.40 (s, 2H), 7.36-7.10 (m, 3H), 3.91 (s, 2H), 1.82- 1.70 (m, 1H),0.89- 0.78 (m, 4H); (M + H)⁺ = 593 + 112 359

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.30 (s, 1H), 7.65 (dt, J =6.6, 2.1 Hz, 1H), 7.65-7.53 (m, 2H), 7.58-7.46 (m, 3H), 7.50-7.41 (m,4H), 7.29-7.16 (m, 3H), 4.11 (s, 2H), 3.14 (d, J = 2.7 Hz, 1H), 2.21(tt, J = 8.6, 5.6 Hz, 1H), 1.02- 0.91 (m, 2H), 0.71- 0.60 (m, 2H); (M +H)⁺ = 593 +++ 112 360

¹H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.16 (s, 1H), 7.72-7.61 (m,2H), 7.55-7.43 (m, 3H), 7.39 (s, 2H), 7.34- 7.21 (m, 3H), 7.10 (dd, J =6.9, 1.3 Hz, 2H), 6.92-6.84 (m, 1H), 3.90 (s, 2H), 3.74 (s, 3H), 1.81-1.69 (m, 1H), 0.89- 0.79 (m, 4H); (M + H)⁺ = 605 + 112 361

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.31 (s, 1H), 7.72-7.60 (m,2H), 7.64-7.48 (m, 2H), 7.53-7.43 (m, 2H), 7.41 (s, 2H), 7.36- 7.27(m,1H), 7.20 (t, J = 7.8 Hz, 1H), 7.07 (dd, J = 2.5, 1.7 Hz, 1H), 6.93(dddd, J = 24.5, 8.3,2.1, 0.9 Hz, 2H), 4.12 (s, 2H), 3.76 (s, 3H), 2.20(tt, J = 8.5, 5.6 Hz, 1H), 1.01-0.90 (m, 2H), 0.70-0.57 (m, 2H); (M +H)⁺ = 605 +++ 112 362

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.69-7.54 (m,2H), 7.58 (s, 2H), 7.50 (dd, J = 7.6, 2.3 Hz, 1H), 7.33 (dd, J = 10.7,8.6 Hz, 1H), 7.24 (s, 3H), 7.29-7.13 (m, 2H), 7.04 (dd, J = 8.2, 1.6 Hz,1H), 4.15 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.32 (s, 3H), 1.20-0.96 (m,1H), 0.37-0.27 (m, 2H), 0.28-0.16 (m, 2H); (M + H)⁺ = 621 +++ 145 363

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.67-7.59 (m,2H), 7.61-7.42 (m, 4H), 7.43 (s, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.26-7.12 (m, 3H), 4.11 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.30 (s, 3H),1.18-1.01 (m, 1H), 0.36-0.27 (m, 2H), 0.24-0.17 (m, 2H); (M + H)⁺ = 603+++ 145 364

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.28 (s, 1H), 7.63-7.45 (m,4H), 7.43 (s, 2H), 7.44- 7.21 (m, 5H), 7.14 (t, J = 7.8 Hz, 1H), 4.10(s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.15- 1.02 (m, 0H), 0.36- 0.15 (m,4H); (M + H)⁺ = 625 +++ 145 365

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.74-7.62 (m,3H), 7.66-7.56 (m, 1H), 7.55 (s, 2H), 7.54- 7.43 (m, 1H), 7.47- 7.38 (m,2H), 7.29- 7.16 (m, 2H), 7.21- 7.12 (m, 1H), 7.07 (dd, J = 8.1, 1.6 Hz,1H), 4.18 (s, 2H), 3.15 (dd, J = 9.4,5.6 Hz, 2H), 1.23-1.06 (m, 1H),0.37-0.17 (m, 4H); (M + H)⁺ = 607 +++ 145 366

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.70-7.58 (m,2H), 7.55 (s, 2H), 7.56- 7.41 (m, 2H), 7.41- 7.23 (m, 4H), 7.17- 6.99(m, 2H), 4.15 (s, 2H), 3.15 (dd, J = 5.8, 4.1 Hz, 2H), 1.21- 1.00 (m,1H), 0.37- 0.25 (m, 2H), 0.27- 0.16 (m, 2H); (M + H)⁺ = 625 +++ 145 367

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.69-7.30 (m,11H), 7.17 (dd, J = 11.3, 1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H),4.16 (s, 2H), 3.19-3.11 (m, 2H), 1.19-1.05 (m, 1H), 0.37-0.26 (m, 2H),0.26-0.16 (m, 2H); (M + H)⁺ = 607 +++ 145 368

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (s, 1H), 7.65-7.17 (m,11H), 7.27 (s, 2H), 4.14 (s, 2H), 3.19-3.11 (m, 3H), 1.18-0.96 (m, 1H),0.37-0.27 (m, 2H), 0.23-0.14 (m, 2H); (M + H)⁺ = 607 + 145 369

¹H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.80 (s, 2H), 8.27 (s, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.60- 7.47 (m, 3H), 7.39- 7.21 (m, 2H), 7.12(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 5.93- 5.87(m, 1H), 4.14- 4.01 (m, 3H), 3.75- 3.68 (m, 2H), 3.25 (t, J = 6.0 Hz,2H), 3.15 (dd, J = 7.2, 5.8 Hz, 4H), 1.12 (dddd, J = 15.0, 10.0, 5.0,2.1 +++ 145 Hz, 1H), 0.37-0.28 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ =612 370

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.76-7.66 (m,4H), 7.65-7.57 (m, 1H), 7.55-7.38 (m, 3H), 7.36-7.13 (m, 6H), 4.18 (s,2H), 3.17 (d, J = 6.9 Hz, 2H), 1.23- 0.98 (m, 1H), 0.38- 0.17 (m, 4H);(M + H)⁺ = 589 +++ 141 371

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.64(ddq, J = 7.3, 3.5, 2.3, 1.8 Hz, 2H), 7.59-7.46 (m, 1H), 7.43-7.29 (m,2H), 7.30-7.12 (m, 3H), 7.12-7.02 (m, 1H), 4.20 (s, 2H), 3.20-3.09 (m,2H), 1.23-0.93 (m, 0H), 0.38-0.25 (m, 2H), 0.29-0.16 (m, 2H); (M + H)⁺ =624 +++ 141 372

¹H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.74-7.65 (m, 2H), 7.36 (dt, J= 7.6, 1.5 Hz, 1H), 7.33- 7.18 (m, 7H), 4.09 (s, 2H), 3.14 (d, J = 6.9Hz, 2H), 2.89 (tt, J = 9.8, 7.5 Hz, 1H), 1.96- 1.84 (m, 1H), 1.71- 1.48(m, 3H), 1.42- 1.25 (m, 1H), 1.16- 1.03 (m, 1H), 0.36- 0.15 (m, 4H);(M + H)⁺ = 563 +++ 146 373

(M + H)⁺ = 599 +++ 146 374

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.44 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.27-7.16 (m, 2H), 7.20- 7.11 (m, 2H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 4.10(s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.78-2.66 (m, 1H), 1.72 (dd, J = 9.7,6.4 Hz, 2H), 1.61 (d, J = 11.8 Hz, 3H), 1.37- 1.23 (m, 2H), 1.15 (s,2H), 1.20-1.03 +++ 146 (m, 2H), 0.38-0.29 (m, 2H), 0.26-0.17 (m, 2H);(M + H)⁺ = 613 375

¹H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.56(s, 2H), 7.52-7.38 (m, 2H), 7.23-7.09 (m, 2H), 7.04 (dd, J = 8.1, 1.6Hz, 1H), 4.09 (s, 2H), 3.16-3.09 (m, 3H), 2.07 (d, J = 3.8 Hz, 2H),1.90-1.79 (m, 2H), 1.85 (s, 4H), 1.69-1.64 (m, 3H), 1.52 (d, J = 12.9Hz, 3H), 1.42 (d, J = 12.6 Hz, 2H), 1.18-1.02 (m, 1H), 0.35-0.24 (m,2H), 0.25-0.14 ++ 146 (m, 2H); (M + H)⁺ = 665 376

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.31 (s, 1H), 7.96-7.81 (m,3H), 7.64 (td, J = 7.9, 5.8 Hz, 2H), 7.56 (s, 2H), 7.13 (dd, J = 11.4,1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.17 (s, 2H), 3.18 (d, J =6.9 Hz, 2H), 1.31- 1.00 (m, 1H), 0.39- 0.25 (m, 2H), 0.29- 0.18 (m, 2H);(M + H)⁺ = 639 +++ 141 377

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.69-7.56 (m, 3H), 7.58 (s,2H), 7.49 (ddd, J = 8.4, 7.7, 6.2 Hz, 1H), 7.43- 7.29 (m, 2H), 7.30-7.13 (m, 3H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H),3.31 (s, 1H), 3.16 (d, J = 6.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.15(td, J = 7.4,5.6 Hz, 1H), 0.38- 0.20 (m, 4H); (M + H)⁺ = 653 − 141 378

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.27 (s, 1H), 7.67-7.54 (m,1H), 7.55 (s, 2H), 7.46- 7.36 (m, 2H), 7.22- 7.06 (m, 2H), 7.02 (dd, J =8.1, 1.6 Hz, 1H), 5.81-5.66 (m, 1H), 5.00-4.87 (m, 2H), 4.13 (s, 2H),3.15 (d, J = 6.9 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.27-2.17 (m, 2H),1.24-1.05 (m, 1H), 0.38-0.26 (m, 2H), 0.29-0.16 (m, 2H); (M + H)⁺ = 585+++ 146 379

(M + H)⁺ = 613 +++ 145 380

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.60-7.47 (m, 3H), 7.32 (s, 1H), 7.29-7.13 (m, 2H), 7.04(dd, J = 8.1, 1.6 Hz, 1H), 5.91 (d, J = 16.9 Hz, 1H), 4.33 (s, 1H), 4.13(s, 2H), 4.06 (s, 1H), 3.79 (s, 1H), 3.61 (s, 1H), 3.16 (d, J = 6.9 Hz,2H), 2.25 (s, 1H), 2.02 (s, 1H), 2.11- 1.75 (m, 1H), 1.22- 1.05 (m, 1H),0.74 (s, +++ 145 3H), 0.72 (s, 1H), 0.38-0.28 (m, 2H), 0.26-0.17 (m,2H); (M + H)⁺ = 680 381

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.54 (s, 2H), 7.48-7.30 (m, 2H), 7.21-7.05 (m, 2H), 7.01(dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),2.60-2.49 (m, 1H), 2.32 (dd, J = 13.2, 7.9 Hz, 1H), 1.48 (dp, J = 13.5,6.9 Hz, 1H), 1.37-1.18 (m, 1H), 1.17-1.00 (m, 1H), 0.89-0.77 (m, 3H),0.70 (d, J = 6.6 Hz, 3H), 0.37- 0.28 (m, 2H), 0.25- 0.16 (m, 2H); (M +H)⁺ = 601 +++ 146 382

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.62 (t, J =7.9 Hz, 1H), 7.54 (s, 2H), 7.48-7.30 (m, 2H), 7.21-7.05 (m, 2H), 7.01(dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H),2.60-2.49 (m, 1H), 2.32 (dd, J = 13.2, 7.9 Hz, 1H), 1.48 (dp, J = 13.5,6.9 Hz, 1H), 1.37-1.18 (m, 1H), 1.17-1.00 (m, 1H), 0.89-0.77 +++ 146 (m,3H), 0.70 (d, J = 6.6 Hz, 3H), 0.37- 0.28 (m, 2H), 0.25- 0.16 (m, 2H);(M + H)⁺ = 585 383

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.68-7.58 (m,1H), 7.56 (s, 2H), 7.46- 7.30 (m, 2H), 7.20- 7.06 (m, 2H), 7.03 (ddd, J= 8.4, 6.8, 1.6 Hz, 1H), 4.12 (d, J = 5.3 Hz, 2H), 3.19- 3.02 (m, 3H),1.09- 1.02 (d, J = 6.9 Hz, 6H), 0.81 (t, J = 7.3 Hz, 1H), 0.38-0.28 (m,2H), 0.25-0.17 (m, 2H); (M + H)⁺ = 573 +++ 146 384

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.25 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.58 (s, 2H), 7.50-7.35 (m, 2H), 7.28-7.19 (m, 2H),7.21-7.11 (m, 2H), 7.16-7.01 (m, 3H), 6.98 (dd, J = 8.1, 1.6 Hz, 1H),4.35 (q, J = 7.2 Hz, 1H), 4.08 (s, 2H), 3.13 (dd, J = 7.0, 4.0 Hz, 2H),1.41 (d, J = 7.2 Hz, 3H), 1.20- 0.96 (m, 1H), 0.31 (dt, J = 9.1, 2.9 Hz,2H), 0.24-0.15 (m, 2H); (M + H)⁺ = 635 +++ 146 385

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.38 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.21-7.08 (m, 2H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 6.94 (dd, J = 7.4, 2.2 Hz,1H), 4.09 (s, 2H), 3.13 (d, J = 6.9 Hz, 2H), 1.97 (tt, J- 8.5, 5.2 Hz,1H), 1.18- 1.04 (m, 1H), 0.94- 0.83 (m, 2H), 0.54- 0.40 (m, 2H), 0.36-0.25 (m, 2H), 0.26- +++ 146 0.15 (m, 2H); (M + H)⁺ = 571 386

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.47 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.30-7.14 (m, 2H), 7.12- 6.98 (m, 2H), 4.11 (s, 2H), 3.14 (d, J = 6.9 Hz,2H), 2.44 (d, J = 1.6 Hz, 2H), 1.11 (ddt, J = 10.3, 7.7, 2.9 Hz, 1H),0.80-0.75 (m, 9H), 0.36-0.25 (m, 2H), 0.27-0.15 (m, 2H); (M + H)⁺ = 601+++ 146 387

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.84 (s, 1H), 8.30 (s, 1H),7.69- 7.56 (m, 3H), 7.58 (s, 2H), 7.56-7.49 (m, 4H), 7.39 (dd, J = 10.6,8.5 Hz, 1H), 7.16 (dd, J = 11.4, 1.5 Hz, 1H), 7.06 (dd, J = 8.1, 1.6 Hz,1H), 4.39 (s, 2H), 4.16 (s, 2H), 3.95 (d, J = 12.9 Hz, 2H), 3.60 (t, J =11.9 Hz, 2H), 3.26 (s, 1H), 3.17 (d, J = 6.8 Hz, +++ 146 2H), 3.07 (s,1H), 1.22-1.04 (m, 1H), 0.38-0.29 (m, 2H), 0.26-0.17 (m, 2H); (M + H)⁺ =706 388

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.43 (ddd, J = 10.1, 5.8, 2.4 Hz, 2H), 7.24-7.09 (m, 2H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 4.14 (s, 2H), 3.17 (d, J =6.9 Hz, 2H), 2.72-2.56 (m, 3H), 2.36-2.17 (m, 2H), 1.65-1.39 (m, 5H),1.25-1.05 (m, 1H), 0.40-0.30 (m, 2H), 0.26-0.18 (m, +++ 146 2H); (M +H)⁺ = 655 389

¹H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.74-7.61 (m, 2H), 7.58-7.44(m, 2H), 7.37 (dd, J = 10.7, 8.6 Hz, 1H), 7.31 (ddt, J = 10.3, 2.9, 1.5Hz, 1H), 7.29- 7.17 (m, 2H), 7.17- 7.04 (m, 2H), 4.18 (s, 2H), 3.17 (d,J = 6.9 Hz, 2H), 2.32 (s, 3H), 1.21-1.06 (m, 1H), 0.38-0.26 (m, 2H),0.28-0.17 (m, 2H); (M + H)⁺ = 638 ++ 141 390

(M + H)⁺ = 628 +++ 146 391

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.26 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.55 (s, 2H), 7.45 (ddd, J = 8.5, 5.0, 2.2 Hz, 1H), 7.31(dd, J = 7.3,2.3 Hz, 1H), 7.23-7.09 (m, 2H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 4.12 (s, 2H), 3.89 (dt, J = 11.3,2.9 Hz, 2H), 3.39 (td, J =11.2,3.5 Hz, 2H), 3.16 (d, J = 6.9 Hz, 2H), 2.98 (tt, J = 10.2, 5.0 Hz,1H), 1.50 (td, J = 11.4, +++ 146 10.3,4.0 Hz, 4H), 1.25-1.00 (m, 1H),0.38-0.29 (m, 2H), 0.30-0.17 (m, 2H); (M + H)⁺ = 615 392

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.57(s, 2H), 7.24 (dd, J = 8.3, 7.6 Hz, 1H), 7.15 (dd, J = 11.3, 1.6 Hz,1H), 7.05 (dd, J = 8.2, 1.6 Hz, 1H), 7.03-6.92 (m, 2H), 6.85 (t, J = 1.9Hz, 1H), 4.10 (s, 2H), 3.48-3.3 (m, 1H), 3.14 (d, J = 6.9 Hz, 2H),2.68-2.53 (m, 2H), 2.47-2.27 (m, 2H), 1.80 (d, J = 12.4 Hz, 2H), 1.45 d,J = 12.4, 4.0 Hz, +++ 145 2H), 1.19-1.04 (m, 1H), 0.36-0.28 (m, 2H),0.23-0.16 (m, 2H); (M + H)⁺ = 664 393

¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.72-7.64 (m, 2H), 7.68-7.54(m, 2H), 7.59 (s, 2H), 7.55-7.30 (m, 6H), 7.21 (dd, J = 11.4, 1.6 Hz,1H), 7.10 (dd, J = 8.1, 1.6 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.18 (s,2H), 3.29 (s, 2H), 3.18 (d, J = 6.9 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H),1.23- 1.08 (m, 1H), 0.39- 0.28 (m, 2H), 0.32- 0.21 (m, 2H); − 141 (M +H)⁺ = 617 394

1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.27 (s, 1H), 7.67 (t, J =7.9 Hz, 1H), 7.59 (s, 2H), 7.25 (dd, J = 8.3, 7.6 Hz, 1H), 7.16 (dd, J =11.4, 1.6 Hz, 1H), 7.10-6.96 (m, 3H), 6.87 (dd, J = 2.6, 1.5 Hz, 1H),4.10 (s, 2H), 3.18-3.09 (m, 6H), 1.95 (tt, J = 14.1,5.7 Hz, 4H),1.23-1.00 (m, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ = 632+++ 141 395

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.26 (s, 1H), 7.65 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 11.3,1.6 Hz, 1H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.90 (dt, J = 7.7, 1.1 Hz,1H), 6.70- 6.50 (m, 2H), 4.12 (s, 2H), 3.59 (t, J = 13.3 Hz, 2H), 3.4-3.29 (m, 2H), 2.31- 2.29 (m, 2H), 3.14 (d, J = 6.9 Hz, 2H), 1.21- 1.02(m, 1H), 0.38- + 141 0.26 (m, 2H), 0.24- 0.14 (m, 2H); (M + H)⁺ = 618396

¹H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.56(s, 2H), 7.29-7.20 (m, 1H), 7.13 (dd, J = 11.4, 1.6 Hz, 1H), 7.08-6.90(m, 4H), 4.11 (s, 2H), 3.36 (d, J = 12.8 Hz, 1H), 3.13 (d, J = 6.9 Hz,2H), 2.68 (dd, J = 12.1, 11.0 Hz, 1H), 2.62-2.49 (m, 3H), 2.01-1.75 (m,0H), 1.69 (d, J = 12.9 Hz, 1H), 1.57-1.32 (m, 3H), 1.19-1.04 (m, 1H),0.36-0.27 (m, +++ 141 2H), 0.24-0.15 (m, 2H); (M +H) = 664 397

¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.27 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.24 (dd, J = 8.2, 7.6 Hz, 1H), 7.18-6.94 (m,4H), 6.89 (dd, J = 2.6, 1.5 Hz, 1H), 4.11 (s, 2H), 3.37 (t, J = 11.9 Hz,2H), 3.19- 3.08 (m, 2H), 3.00 (t, J = 5.5 Hz, 2H), 1.98 (tt, J = 13.8,6.4 Hz, 2H), 1.72-1.52 (m, 2H), 1.18-1.04 (m, 1H), 0.37-0.25 (m, +++ 1412H), 0.25-0.16 (m, 2H); (M + H)⁺ = 632 398

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.77 (d, J =1.8 Hz, 1H), 7.68-7.57 (m, 2H), 7.57-7.50 (m, 2H), 7.44 (t, J = 7.8 Hz,1H), 7.12-6.99 (m, 2H), 6.11 (s, 1H), 4.12 (s, 1H), 3.14 (d, J = 6.8 Hz,2H), 1.39 (tt, J = 8.4,5.3 Hz, 1H), 1.18-1.04 (m, 1H), 0.70 (dq, J =10.0, 5.1 Hz, 1H), 0.54-0.42 (m, 1H), 0.37-0.09 (m, 5H); (M + H)⁺ = 651+++ 141 399

¹H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.21 (s, 1H), 7.70-7.63 (m,2H), 7.63-7.56 (m, 1H), 7.56 (s, 2H), 7.49- 7.36 (m, 2H), 7.06- 6.95 (m,2H), 6.03 (s, 1H), 3.85 (s, 2H), 2.42 (d, J = 6.8 Hz, 2H), 1.48 (tt, J =8.3, 5.3 Hz, 1H), 1.01- 0.86 (m, 2H), 0.67 (dq, J = 10.0, 5.1 Hz, 1H),0.49-0.33 (m, 4H), 0.27-0.04 (m, 5H); (M + H)⁺ = 651 + 141 400

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.27 (s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.56 (s, 2H), 7.31-7.09 (m, 4H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 4.16-4.05 (m, 3H), 3.85 (ddd, J = 10.6, 8.6, 1.6 Hz, 1H), 3.15 (d,J = 6.7 Hz, 2H), 2.29-1.99 (m, 0H), 1.70 (tdd, J = 12.0, 8.0, 4.9 Hz,2H), 1.43 (dtd, J = 13.8, 7.8, 4.2 Hz, 1H), 1.26- 0.93 (m, 1H), 0.37-0.16 (m, 4H); (M + H)⁺ = 637 +++ 120 401

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.68-7.46 (m,5H), 7.28 (dd, J = 9.5, 8.7 Hz, 1H), 7.12 (dd, J = 11.3, 1.6 Hz, 1H),7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), 3.14 (d, J = 6.2 Hz, 3H),2.07 (s, 3H), 1.11 (dddd, J = 12.5, 8.0, 4.9, 1.9 Hz, 1H), 0.37-0.27 (m,2H), 0.27-0.16 (m, 2H); (M + H)⁺ = 569 +++ 145 402

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.69-7.44 (m,6H), 7.27 (dd, J = 9.4, 8.7 Hz, 1H), 7.15 (dd, J = 11.4, 1.6 Hz, 1H),7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13 (s, 2H), 3.16 (d, J = 6.8 Hz, 2H),1.27 (s, 9H), 1.18-0.96 (m, 1H), 0.37-0.27 (m, 2H), 0.27-0.16 (m, 2H);(M + H)⁺ = 611 +++ 145 403

¹H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.29 (s, 1H), 7.78-7.68 (m,2H), 7.68-7.58 (m, 2H), 7.56 (s, 2H), 7.47 (dd, J = 3.7, 1.2 Hz, 1H),7.37 (dd, J = 9.4, 8.7 Hz, 1H), 7.19-7.11 (m, 2H), 7.04 (dd, J = 8.1,1.6 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.20- 1.05 (m, 1H),0.38- 0.27 (m, 2H), 0.27- 0.17 (m, 2H); (M + H)⁺ = 637 +++ 145 404

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.27 (s, 1H), 7.68-7.56 (m,3H), 7.56 (s, 1H), 7.38- 7.29 (m, 1H), 7.13 (dd, J = 11.3, 1.5 Hz, 1H),7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.34 (s, 2H), 4.14 (s, 2H), 3.31 (s,3H), 3.15 (d, J = 6.5 Hz, 2H), 1.33- 0.83 (m, 0H), 0.37- 0.27 (m, 2H),0.24- 0.16 (m, 2H); (M + H)⁺ = 599 +++ 145 405

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H),7.74- 7.60 (m, 3H), 7.57 (s, 2H), 7.43-7.34 (m, 2H), 7.16 (dd, J = 11.3,1.6 Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.16 (s, 2H), 3.67 (d, J =0.5 Hz, 3H), 3.16 (d, J = 6.9 Hz, 2H), 1.26-0.96 (m, 1H), 0.38-0.28 (m,2H), 0.25-0.17 (m, 2H); (M + H)⁺ = 635 +++ 145 406

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (s, 1H), 7.82 (d, J =8.1 Hz, 1H), 7.52 (s, 2H), 7.42-7.31 (m, 2H), 7.21-7.11 (m, 2H), 6.94(dd, J = 7.4, 2.2 Hz, 1H), 4.08 (s, 2H), 3.14 (d, J = 6.9 Hz, 2H), 1.97(tt, J = 8.4, 5.2 Hz, 1H), 1.19- 1.04 (m, 2H), 0.96- 0.83 (m, 2H), 0.54-0.40 (m, 2H), 0.37- 0.26 (m, 2H), 0.26-0.15 (m, 2H); (M + H)⁺ = 588 +++146 407

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.28 (s, 1H), 7.85 (d, J =8.2 Hz, 1H), 7.61-7.43 (m, 6H), 7.35 (dd, J = 11.3, 8.6 Hz, 1H),7.22-7.10 (m, 2H), 6.82 (dt, J = 3.6, 1.1 Hz, 1H), 4.15 (s, 2H), 3.17(d, J = 6.9 Hz, 2H), 1.20-0.98 (m, 1H), 0.38-0.29 (m, 2H), 0.28-0.17 (m,2H); (M + H)⁺ = 644 +++ 145 408

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.72 (dd, J =6.9, 2.3 Hz, 1H), 7.68-7.58 (m, 2H), 7.56 (s, 2H), 7.36 (dd, J = 9.4,8.7 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 7.14 (dd, J = 11.3, 1.6 Hz, 1H),7.04 (dd, J = 8.1, 1.6 Hz, 1H), 6.83 (dt, J = 3.4, 1.1 Hz, 1H), 4.16 (s,2H), 3.16 (d, J = 6.9 Hz, 2H), 1.20- 1.05 (m, 1H), 0.38- 0.27 (m, 2H),0.27- 0.16 (m, 2H); (M + H)⁺ = 651 +++ 145 409

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68-7.57 (m, 2H), 7.56 (s,2H), 7.52 (ddd, J = 8.7, 5.0, 2.3 Hz, 1H), 7.28 (dd, J = 9.4, 8.7 Hz,1H), 7.12 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H),4.89 (d, J = 6.3 Hz, 1H), 4.13 (s, 2H), 3.57 (q, J = 6.6 Hz, 2H), 3.15(d, J = 6.7 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.11 (dddd, J = 15.0,10.0, 5.0, 2.2 Hz, 1H), 0.37- 0.27 (m, 2H), 0.24-0.16 +++ 145 (m, 2H);(M + H)⁺ = 599 410

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.72-7.57 (m,3H), 7.55 (s, 2H), 7.33 (t, J = 9.0 Hz, 1H), 7.12 (dd, J = 11.4, 1.6 Hz,1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.53 (s, 1H), 4.14 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 1.18-1.04 (m, 1H), 0.37-0.27 (m, 2H), 0.24-0.16 (m,2H); M + H)⁺ = 556 +++ 145 411

(M + H)⁺ = 637 +++ 145 412

¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.68-7.51 (m, 4H), 7.30 (dd, J= 9.4, 8.6 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.1,1.6 Hz, 1H), 5.39 (s, 1H), 4.13 (s, 2H), 3.18- 3.11 (m, 2H), 1.96- 1.79(m, 4H), 1.79- 1.59 (m, 4H), 1.10 (s, 1H), 0.36-0.15 (m, 4H); (M + H)⁺ =639 +++ 145 413

(M + H)⁺ = 641 +++ 145 414

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.30 (s, 1H), 7.76 (dd, J =6.7, 2.3 Hz, 1H), 7.72-7.58 (m, 2H), 7.57 (s, 2H), 7.39 (t, J = 9.0 Hz,1H), 7.14 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.6 Hz, 1H),4.99-4.81 (m, 4H), 4.15 (s, 2H), 3.16 (d, J = 7.2 Hz, 2H), 1.20-1.05 (m,1H), 0.38-0.27 (m, 2H), 0.27-0.17 (m, 2H); (M + H)⁺ = 629 +++ 145 415

¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.74-7.53 (m, 4H), 7.39-7.26(m, 1H), 7.13 (dd, J = 11.4, 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz,1H), 6.69 (s, 1H), 4.78-4.71 (m, 2H), 4.62-4.55 (m, 2H), 4.15 (s, 2H),3.15 (d, J = 6.5 Hz, 2H), 1.18- 1.03 (m, 1H), 0.37- 0.25 (m, 2H), 0.25-0.13 (m, 2H); (M + H)⁺ = 627 +++ 145 416

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.68-7.58 (m,2H), 7.58-7.54 (m, 3H), 7.36-7.26 (m, 1H), 7.15 (dd, J = 11.3, 1.6 Hz,1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H), 4.43 (d,J = 5.7 Hz, 2H), 4.14 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.62 (s, 3H),1.12 (s, 1H), 0.38- 0.28 (m, 2H), 0.25- 0.17 (m, 2H); (M + H)⁺ = 625 +++145 417

¹H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.36 (s, 1H), 8.32 (s, 1H),7.79- 7.55 (m, 5H), 7.40 (t, J = 9.0 Hz, 1H), 7.14 (dd, J = 11.3, 1.6Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.40 (s, 2H), 4.16 (s, 2H),3.17 (d, J = 6.9 Hz, 2H), 1.96 (s, 4H), 1.23-1.00 (m, 0H), 0.39-0.29 (m,2H), 0.26-0.18 (m, 2H); (M + H)⁺ = 638 +++ 145 418

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.27 (s, 1H), 7.68-7.58 (m,3H), 7.57 (d, J = 4.7 Hz, 2H), 7.37-7.27 (m, 1H), 7.13 (dd, J = 11.5,1.5 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 5.92 (s, 1H), 4.14 (s, 2H),3.91- 3.83 (m, 2H), 3.83- 3.72 (m, 2H), 3.15 (d, J = 6.7 Hz, 2H), 2.24-2.13 (m, 2H), 0.98 (s, 1H), 0.57 (s, 1H), 0.37-0.28 (m, 2H), 0.25-0.16(m, 2H); (M + H)⁺ = 641 +++ 145 419

¹H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.29 (s, 1H), 7.72-7.59 (m,3H), 7.57 (s, 2H), 7.37 (t, J = 9.3 Hz, 1H), 7.15 (dd, J = 11.4, 1.6 Hz,1H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.23- 4.10 (m, 3H), 4.00- 3.85 (m,3H), 3.16 (d, J = 7.0 Hz, 2H), 2.61- 2.13 (n, 13H), 1.12 (dddd, J =13.0, 8.0, 4.9, 1.9 Hz, 1H), 0.38- 0.17 (m, 4H); (M + H)⁺ = 643 +++ 145420

¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H),7.61-7.54 (m, 3H), 7.51 (ddd, J = 8.6, 5.0, 2.3 Hz, 1H), 7.28 (dd, J =9.4, 8.7 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.2,1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.14 (d, J = 6.9 Hz, 2H), 2.07(s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.18-1.07 (m, 1H), 0.38-0.29 (m, 2H),0.25-0.17 (m, 2H); (M + H)⁺ = 597 + 145 421

(M + H)⁺ = 639 +++ 145 422

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.27 (s, 1H), 7.65-7.38 (m,5H), 7.34-7.21 (m, 4H), 4.11 (s, 2H), 3.14 (dd, J = 5.8, 3.3 Hz, 2H),2.06 (s, 3H), 1.17- 1.03 (m, 1H), 0.36- 0.25 (m, 2H), 0.25- 0.14 (m,2H); (M + H)⁺ = 551 +++ 145 423

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.51 (m, 4H), 7.34-7.24 (m, 1H), 7.14 (dd, J = 11.4,1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 4.13 (s, 2H), 3.95 (dd, J =8.1, 7.3 Hz, 1H), 3.87-3.68 (m, 2H), 3.58 (dd, J = 8.1, 6.5 Hz, 1H),3.34- 3.22 (m, 6H), 3.15 (d, J = 6.9 Hz, 2H), 2.25 (dddd, J = 12.1, 8.5,7.4, 6.0 Hz, 1H), 1.92 (ddt, J = 12.1, 7.8, 6.6 Hz, 1H), 1.12 (s, 1H),0.37-0.28 (m, 2H), 0.25-0.16 (m, 2H); M + H)⁺ = 625 +++ 145 424

¹H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.14 (s, 1H), 7.80 (d, J =8.2 Hz, 2H), 7.05 (s, 2H), 5.96 (s, 1H), 3.81 (s, 3H); (M + H)⁺ = 318 −147 425

(M + H)⁺ = 306 − 147 426

¹H NMR (400 MHz, DMSO-d 6.09-7.99 (m, 2H), 7.92 (s, 1H), 7.41-7.30 (m,2H); (M + H)⁺ = 358 + 150 427

¹H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.40 (s, 1H), 8.05-7.93 (m,4H), 7.63-7.52 (m, 2H); (M + H)⁺ = 374 + 150 428

¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 0.5 Hz, 1H), 7.65 (t, J = 7.9Hz, 1H), 7.57-7.44 (m, 4H), 7.37-7.31 (m, 2H), 7.13 (dd, J = 11.3, 1.5Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.13(s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 2.82 (p, J = 7.3 Hz, 1H), 2.00-1.87(m, 2H), 1.75-1.47 (m, 6H), 1.35-1.28 (m, 2H), 1.26 (d, J = 19.9 Hz,1H), 1.18-1.07 (m, 1H), 0.38-0.28 (m, 2H), 0.28-0.19 (m, 2H); (M + H)⁺ =633 − 145 429

(M + H)⁺ = 633 + 145 430

(M + H)⁺ = 605 +++ 145 431

(M + H)⁺ = 609 +++ 145 432

(M + H)⁺ = 605 +++ 145 433

(M + H)⁺ = 577 +++ 145 434

(M + H)⁺ = 637 + 145 435

(M + H)⁺ = 605 + 145 436

(M + H)⁺ = 641 +++ 145 437

¹H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.50 (m, 4H), 7.29 (dd, J = 9.4, 8.5 Hz, 1H), 7.13(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s,2H), 3.14 (d, J = 6.9 Hz, 2H), 2.51 (d, J = 5.9 Hz, 2H), 1.11 (dddd, J =15.0, 10.0, 5.1, 2.2 Hz, 1H), 1.05-0.92 (m, 1H), 0.51-0.41 (m, 2H),0.37-0.28 (m, 2H), 0.27-0.16 +++ 145 (m, 4H); (M + H)⁺ = 609 438

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.28 (s, 1H), 7.61 (dt, J =7.9, 1.4 Hz, 1H), 7.56-7.38 (m, 4H), 7.32 (dt, J = 7.7, 1.4 Hz, 1H),7.27 (s, 2H), 7.24 (d, J = 8.9 Hz, 1H), 4.10 (s, 2H), 3.15 (d, J = 6.8Hz, 2H), 2.87 (p, J = 7.2 Hz, 1H), 2.02- 1.49 (m, 8H), 1.10 (tdd, J =12.0, 7.1, 2.4 Hz, 1H), 0.37-0.27 (m, 2H), 0.23-0.14 (m, 2H); (M + H)⁺ =605 ++ 145 439

(M + H)⁺ = 641 ++ 145 440

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.83 (dd, J =6.7, 2.3 Hz, 1H), 7.72 (ddd, J = 8.7, 5.1, 2.3 Hz, 1H), 7.62 (t, J = 7.9Hz, 1H), 7.55 (s, 2H), 7.42 (t, J = 9.1 Hz, 1H), 7.15-7.07 (m, 1H),7.06-6.97 (m, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.18-1.02 (m,1H), 0.36-0.28 (m, 2H), 0.24-0.17 (m, 2H); (M + H)+ = 606 +++ 145 441

¹H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.79 (t, J = 7.8 Hz, 1H),7.51 (dd, J = 6.8, 2.3 Hz, 1H), 7.33 (ddd, J = 8.6, 4.9, 2.3 Hz, 1H),7.08- 6.90 (m, 3H), 5.30 (s, 2H), 5.10 (s, 2H), 4.99 (s, 2H), 4.05 (s,2H), 3.18 (d, J = 6.8 Hz, 2H), 2.85 (p, J = 7.4 Hz, 1H), 2.25 (s, 3H),2.12-1.93 (m, 1H), 1.86-1.54 (m, 7H), 1.17-1.02 (m, 1H), 0.47-0.39 (m,2H), 0.28-0.22 (m, 2H); (M + H)⁺ = 735 − 145 442

(M + H)⁺ = 580 +++ 145 443

¹H NMR (400 MHz, DMSO-d6) δ 13.34- 12.89 (m, 1H), 8.29 (s, 1H),7.71-7.58 (m, 3H), 7.56 (s, 2H), 7.36 (t, J = 8.9 Hz, 1H), 7.18-6.96 (m,2H), 5.77-5.53 (m, 1H), 4.14 (s, 2H), 3.16 (d, J = 6.9 Hz, 2H), 1.60(dd, J = 23.0, 6.5 Hz, 3H), 1.12 (tq, J = 9.8, 3.4, 2.4 Hz, 1H), 0.38-0.28 (m, 2H), 0.25- 0.16 (m, 2H); (M + H)⁺ = 601 +++ 145 444

¹H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.28 (s, 1H), 7.66 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.35 (dd, J = 7.6, 2.3 Hz, 1H), 7.29-7.01 (m,3H), 6.25 (p, J = 2.1 Hz, 1H), 4.12 (s, 2H), 3.18-3.11 (m, 2H),2.49-2.38 (m, 4H), 1.85 (p, J = 7.6 Hz, 2H), 1.12 (tdd, J = 11.3, 6.4,2.0 Hz, 1H), 0.37-0.27 (m, 2H), 0.25-0.16 (m, 2H); (M + H)⁺ = 597 +++145 445

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.60-7.48 (m, 4H), 7.28 (t, J = 9.0 Hz, 1H), 7.14 (dd, J =11.4, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.12 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 2.82 (hept, J = 6.8 Hz, 1H), 1.20 (d, J = 6.9 Hz,6H), 1.12 (tq, J = 9.9, 3.5, 2.2 Hz, 1H), 0.38-0.28 (m, 2H), 0.25-0.17(m, 2H); (M + H)⁺ = 597 +++ 145 446

¹H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.29 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.58-7.49 (m, 4H), 7.28 (dd, J = 9.5, 8.3 Hz, 1H), 7.14(dd, J = 11.3, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 1.6 Hz, 1H), 4.13 (s,2H), 3.36-3.23 (m, 1H), 3.15 (d, J = 6.6 Hz, 2H), 2.34-2.23 (m, 2H),2.19-2.07 (m, 2H), 2.01-1.81 (m, 2H), 1.19-1.04 (m, 1H), 0.37-0.28 (m,2H), 0.25-0.16 (m, 2H); (M + H)+ = 609 +++ 145 447

¹H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.72 (dd, J = 6.9, 2.3 Hz,1H), 7.69- 7.51 (m, 4H), 7.36 (t, J = 9.0 Hz, 1H), 7.27 (d, J = 3.6 Hz,1H), 7.15 (dd, J = 11.3, 1.6 Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H),6.83 (dt, J = 3.6, 1.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H),3.16 (d, J = 6.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.19-1.04 (m, 1H),0.40-0.29 (m, 2H), 0.27-019 (m, 2H); (M + H)⁺ = 679 − 145 448

(M + H)⁺ = 613 +++ 145 449

¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.29 (s, 1H), 7.69-7.60 (m,2H), 7.59-7.47 (m, 4H), 7.42 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 3.6 Hz,1H), 7.14 (dd, J = 11.3, 1.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H),6.81 (dd, J = 3.6, 1.3 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.1 Hz, 2H),2.47- 2.44 (m, 3H, 1.13 (dqd, J = 14.8, 7.2, 5.0 Hz, 1H), 0.38- 0.28 (m,2H) 0.26- 0.15 (m, 2H); (M + H)⁺ = 633 +++ 145 450

(M + H)⁺ = 585 +++ 145 451

2-(5-hydroxy-3- (naphthalen-2-yl)-4- (4-sulfamoylbenzyl)- ¹H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.19 (s, 1H), 8.09(d, 2H, J = 1.6 Hz), 8.00 (d, 1H, J = 8 Hz), 7.86 (d, 1H, J = 8 Hz)7.63- 7.51 (m, 6H), 7.12 (d, 1H, J = 8 Hz), 3.69 (s, 2H); MS (ES) 506.9(M + H)⁺ LCMS RT = 0.88 min. + Ex- ample 69 452

2-(3-(3,4- difluorophenyl)-5- hydroxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.18 (s,1H), 7.85 (d, 2H, J = 8.4 Hz), 7.56 (m, 1H), 7.45-7.41 (m, 4H), 3.99 (s,2H); MS (ES) 492.9 (M + H)⁺ LCMS RT = 0.88 min. ++ Ex- ample 70 453

2-(5-hydroxy-3- (pyridin-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, TFA: VU0657478 (PC-6-098); MS(ES) 457.9 (M + H)⁺ LCMS RT = 0.30 min. + Ex- ample 71 454

2-(3-(6- fluoronaphthalen-1- (57%) yl)-5-hydroxy- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR(d6-DMSO) δ 8.20 (m, 2H), 7.88 (d, 2H, J = 8 Hz), 7.70- 7.55 (m, 5H),7.32 (m, 1H), 7.12 (d, 1H, J = 8 Hz), 3.69 (s, 2H); MS (ES) 524.9 (M +H)⁺ LCMS RT = 0.94 min. + Ex- ample 72 455

2-(3-(3,4- difluorophenyl)-5- methoxy-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.20 (s,1H), 7.81 (d, 2H, J = 8 Hz), 7.54- 7.50 (m, 2H), 7.39-7.36 (m, 3H), 3.69(s, 2H), 3.49 (s, 3H); MS (ES) 506.9 (M + H)⁺ LCMS RT = 0.89 min. ++ Ex-ample 73 456

2-(3-(6-fluoro-3′- methoxy-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)565.0 (M + H)⁺ LCMS RT = 1.08 min. +++ Ex- ample 85 457

2-(3-(3′-chloro-6- fluoro-[1,1′-biphenyl]- 3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)568.9 (M + H)⁺ LCMS RT = 1.16 min. +++ Ex- ample 86 458

2-(3-(3′,6-difluoro- [1,1′-biphenyl]-3-yl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 552.9 (M + H)⁺ LCMS RT= 1.12 min. +++ Ex- ample 87 459

2-(3-(3- isopropoxyphenyl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4- carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.24 (m, 2H), 7.78(d, 2H, J = 8 Hz), 7.44 (d, 2H, J = 8 Hz), 7.39- 7.30 (m, 3H), 7.22 (d,1H, J = 8 Hz), 7.09 (d, 1H, J = 4 Hz), 6.99-6.96 (m, 1H), 4.51 (m, 1H),4.15 (s, 2H), 1.27 (d, 6H, J = 8 Hz); MS (ES) 499.0 +++ Ex- ample 74(M + H)⁺ LCMS RT = 1.07 min. 460

2-(3-(3- (cyclopentyloxy) phenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.55 (m,2H), 8.25 (d, 2H, J = 4 Hz), 7.77 (d, 2H, J = 4 Hz), 7.55- 7.26 (m, 3H),7.22 (d, 1H, J = 8 Hz), 7.09 (d, 1H, J = 8 Hz), 6.99- 6.96 (m, 1H), 4.74(m, 1H), 4.15 (s, 2H), 1.91-1.82 (m, 2H), 1.69-1.58 (m, 4H), +++ Ex-ample 75 1.23 (m, 2H); MS (ES) 525.0 (M +H)⁺ LCMS RT = 1.15 min. 461

2-(4-(4- sulfamoylbenzyl)-3- (3-((tetrahydrofuran- 3-yl)methoxy)phenyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 540.7 (M + H)⁺LCMS RT = 1.13 min. +++ Ex- ample 76 462

2-(3-(3-((3- methoxybenzyl)oxy) phenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 576.9 (M + H)⁺ LCMS RT= 1.02 min. +++ Ex- ample 77 463

2-(4-(4- sulfamoylbenzyl)-3- (3-((tetrahydrofuran- 2-yl)methoxy)phenyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 540.9 (M + H)⁺LCMS RT = 0.76 min. +++ Ex- ample 78 464

2-(3-(3- phenoxyphenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 532.9 (M + H)⁺ LCMS RT= 0.98 min. +++ Ex- ample 79 465

2-(3-(3-(pyridin-3 ylmethoxy)phenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid, TFA MS (ES) 548.0 (M + H)⁺LCMS RT = 0.68 min. +++ Ex- ample 80 466

2-(3-(3-(pyridin-2- ylmethoxy)phenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid TFA; MS (ES) 547.9 (M +H)⁺, LCMS RT = 0.68 min. +++ Ex- ample 81 467

Synthesis of 2-(3-(3- (cyclopentyloxy)-4- methylphenyl)-5-(cyclopropylmethyl)- 4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.07 (s, 1H), 7.53 (d, 2H, J = 8Hz), 7.12- 7.07 (m, 5H), 6.95 (d, 1H, J = 8 Hz), 6.87 (d, 1H, J = 8 Hz),6.63 (s, 1H), 4.16 (m, 1H), 3.90 (s, 2H), 2.93 (m, 2H), 1.87 (s, 3H),+++ Ex- ample 120 1.40-1.29 (m, 8H), 0.91 (m, 1H), 0.11 (m, 2H), 0.014(m, 2H); MS (ES) 593.4 (M + H)⁺, LCMS RT = 0.81 min. 468

2-(3-(5- (cyclopentyloxy)-2- fluorophenyl)-5- (cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(d6-DMSO) δ 8.07 (s, 1H), 7.43 (d, 2H, J = 8 Hz), 7.02- 6.93 (m, 5H),6.73 (m, 1H), 6.60 (m, 1H), 4.40 (m, 1H), 2.93 (m, 2H), 1.59-1.54 (m,2H), 1.52-1.32 (m, 6H), 0.91 (m, 1H), ++ By anal- ogy with Ex- ample 1200.013 (m, 2H), 0.010 (m, 2H); MS (ES) 597.4 (M + H)⁺, LCMS RT = 067 min.469

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- ((tetrahydrofuran-2-yl)methoxy)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.07 (s,1H), 7.44 (m, 1H), 7.35 (s, 2H), 7.05-6.82 (m, 5H), 3.93 (s, 2H), 3.87-3.43 (m, 6H), 2.93 (m, 2H), 1.75-159 (m, 3H), 1.38 (m, 1H), 0.90 (m,1H), 0.013 (m, 2H) 0.010 (m, +++ Ex- ample 121 2H); MS (ES) 630.9 (M +H)⁺, LCMS RT = 1.10 min. 470

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- ((tetrahydrofuran-3-yl)methoxy)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.07 (s,1H), 7.44 (m, 1H), 7.35 (s, 2H), 7.04-7.01 (m, 1H), 6.95-6.91 (m, 3H),6.84-6.82 (m, 1H), 3.92 (s, 2H), 3.52- 3.50 (m, 4H), 3.40- 3.35 (m, 2H),3.20 (m, 1H), 2.93 (m, 2H), 2.4 (m, 1H), 1.77 (m, 1H), +++ Ex- ample 1221.39 (m, 1H), 0.91 (m, 1H), 0.013 (m, 2H) 0.010 (m, 2H); MS (ES) 552.9(M + H)⁺, LCMS RT = 1.12 min. 471

2-(3-(3-cyclopropoxy- 4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid; ¹H- NMR (d6-DMSO) δ 8.07 (s, 1H), 7.46 (m, 1H), 7.37 (s, 2H), 7.19(m, 1H), 7.05- 6.85 (m, 5H), 3.92 (s, 2H), 3.50 (m, 1H), 2.93 (m, 2H),0.91 (m, 1H), 0.013 (m, 2H) 0.010 (m, 2H); MS +++ Ex- ample 123 (ES)586.9 (M + H)⁺, LCMS RT = 1.12 min. 472

2-(5- (cyclopropylmethyl)- 3-(6-fluoro-4′-methyl- [1,1′-biphenyl]-3-yl)-4-(2-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid; ¹H- NMR (d6-DMSO) δ 8.31 (s, 1H), 7.59- 7.35 (m, 11H), 7.17 (m,1H), 4.13 (s, 2H), 3.02 (m, 2H), 2.35 (s, 3H), 1.15 (m, 1H), 0.033 (m,2H) 0.021 (m, 2H); MS (ES) Ex- ample 124 621.4 (M + H)⁺, LCMS RT = 0.79min. 473

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((5- (trifluoromethyl) furan-2-yl)methoxy)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 694.9 (M + H)⁺, LCMSRT = 1.20 min. +++ Ex- ample 125 474

2-(5-(naphthalen-2- yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (d6-DMSO) δ 8.24 (s,1H). 8.13 (s, 1H), 7.91-8.03 (m, 4H), 7.80 (d, J = 8.2 Hz, 2H),7.52-7.58 (m, 3H), 7.32 (s, 2H), 4.25 (s, 2H); MS (ES) 491 (M + H)⁺ LCMSRT 1.04 min. +++ Ex- ample 82 475

2-(5-(pyridin-3-yl)-4- (4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole-4-carboxylic acid; MS (ES) 442 (M + H)⁺ LCMS RT 0.64 min. ++ Ex- ample 83476

2-(3-(6-fluoro-4′- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(d6-DMSO) δ 8.27 (d, J = 9.24 Hz, 2H), 7.76-7.78 (m, 4H), 7.29-7.46 (m,8H), 4.2 (s, 2H), 2.35 (s, 3H); MS (ES) 549 (M + H)⁺ LCMS RT 1.27 min.+++ Ex- ample 84 477

2-(3-(3- (cyclopentyloxy) phenyl)-5- (cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(CDCl₃) δ 8.10 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.23-7.31 (m, 4H),7.02-7.07 (m, 2H), 6.88 (dd, J = 1.76, 1.8 Hz, 1H) 4.97 (s, 2H), 4.11(s, 2H), 3.15 (d, J = 6.64 Hz, 2H), 1.58-1.79 (m, 9H), 1.12-1.16 (m,1H), 0.43 (d, J = 8 Hz, 2H), 0.21 (d, J = 5.4 Hz, 2H), MS (ES) 579 (M +H)⁺ LCMS RT 1.15 min. Ex- ample 126 478

2-(5- (cyclopropylmethyl)- 3-(5-fluoro-3′- methoxy-[1,1′-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (CDCl₃) δ 8.10 (s, 1H) 7.86 (d, J = 8.32 Hz,2H, ) 7.23- 7.29 (m, 7H), 7.00 (d, J = 7.12 Hz, 1H), 6.91 (dd, J = 1.881.88 Hz, 1H), 6.60 (t, J = 3.92 Hz, 1H), 4.96 (s, 2H), 4.11 (s, 2H), ),3.87 (s, 3H), 3.21 (d, J = 6.64 Hz, 2H) 1.17-1.25 (m, 1H) 0.47 (d, J =7.28 Hz, 2H), 0.24 (d, J = 5.2 Hz, 2H), MS: (ES) 619 (M + H)⁺ LCMS RT1.32 min. +++ Ex- ample 143 479

2-(5- (cyclopropylmethyl)- 3-(4′,5-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)607 (M + H)⁺ LCMS RT 1.35 min. +++ Ex- ample 144 480

2-(3-(3-(benzyloxy)- 4-fluorophenyl)-5- (cyclopropylmethyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(CDCl₃) δ 8.11 (s, 1H), 7.84 (d, J = 8 Hz, 2H), 7.24- 7.38 (m, 8H), 7.15(d, J = 7.4 Hz, 1H) 7.08 (d, J = 8 Hz, 2H), 5.01 (s, 2H), 4.95 (s, 3H),4.02 (s, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.11- 1.15 (m, 1H), 0.42 (d, J =7 Hz, 2H), 0.21 (d, J = 5.24 Hz, 2H); MS (ES) 619 (M + H)⁺ LCMS RT =1.28 min. +++ Ex- ample 127 481

2-(5- (cyclopropylmethyl)- 4-(4- sulfamoylbenzyl)-3- (3-(4-(trifluoromethyl) phenoxy)phenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (CDCl₃) δ 8.11 (s, 1H), 7.8 (d, J = 8 Hz,2H), 7.6 (d, J = 8 Hz, 2H), 7.21-7.40 (m, 5H), 7.01-7.06 (m, 3H), 5.04(s, 2H), 4.08 (s, 2H), 3.16 (d, J = 6 Hz, 2H), 1.09- 1.15 (m, 1H) 0.42(d, J =
 8. Hz, 2H), 0.21 (d, J = 5 Hz, 2H), MS (ES) 655 (M + H)⁺ LCMS RT= 1.38 min in 2 min method. +++ Ex- ample 128 482

2-(5-cyclopropyl-3- (4′,6-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD): δ 8.27 (s, 1H) 7.85 (d, J = 12 Hz, 2H), ; 7.57- 7.63 (m, 1H),7.5 (d, J = 16 Hz, 1H), 7.29- 7.42 (m, 4H), 7.12- 7.25 (m, 4H), 4.25 (s,2H), 2.32-2.41 (m, 1H), 1.15 (d, J = 12 Hz, 2H), 0.7 (d, J = 9 Hz, 2H);(ES) 593 (M + H)⁺ LCMS RT = 1.28 min in 2 min method. +++ Ex- ample 112483

2-(5-cyclopropyl-3- (6-fluoro-3′-methoxy- [1,1′-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid;¹H-NMR (CDCl₃) δ 8.13 (s, 1H), 7.85 (d, J = 8 Hz, 2H), 7.55- 7.59 (m,1H), 7.35- 7.39 (m, 2H), 7.25- 7.31 (m, 4H), 7.17 (t, J = 18.84 Hz, 1H),7.04 (d, J = 7.56 Hz, 1H), 6.91-6.94 (dd, J = 2, 2 Hz, 1H), 6.73 (s,1H), 5.04 (s, Broad, 2H), 4.17 (s, 2H), 3.87 (s, 3H), 2.23-2.27 (m, 1H),1.12 (d, J = 7 Hz, 2H), 0.73 (d, J = 5 Hz, 2H), MS (ES) 605 (M + H)⁺LCMS RT = +++ Ex- ample 113 1.25 min in 2 min method. 484

2-(5-cyclopropyl-3- (6-fluoro-4′-methyl- [1,1′-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(CDCl₃) δ 8.10 (s, 1H), 7.82 (d, J =
 8. Hz, 2H), 7.5 (dd, J1 = 2; J2 = 2Hz, 1H), 7.41-7.45 (m, 1H), 7.22-7.32 (m, 7H), 7.13 (t, J = 19 Hz, 1H),5.06 (s, 2H), 4.14 (s, 2H), 2.40 (s, 3H), 2.17-2.23 (m, 1H), 1.07 (d, J= 8 Hz, 2H), 0.68 (d, J =
 5. Hz, 2H), MS (ES) 589 (M + H)⁺ +++ Ex- ample114 LCMS RT = 1.31 min in 2 min method. 485

2-(5- (cyclopropylmethyl)- 3-(3-(phenylamino) phenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(CDCl₃) δ 7.96 (1H, s), 7.72 (2H, d, J = 8.3 Hz), 7.23-7.18 (6H, m),7.02-6.99 (4H, m), 6.88 (1H, t, J = 7.4 Hz), 4.02 (2H, s), 3.10 (2H, d,J = 6.8 Hz), 1.01 (1H, m), 0.33 (2H, dd, J = 13.8, 5.8 Hz), 0.14 (2H,dd, J = 10.2, 5.0 Hz); MS (ES) 587.7 (M + H)⁺; LCMS RT = 1.06 min. +++Ex- ample 115 486

2-(3-(4-methyl-3- (pyridin-3-yl)phenyl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.77 (s, 1H),8.72 (s, 1H), 8.40 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 7.92(dd, J = 7.6, 5.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (dd, J = 7.6,1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.21(s, 2H), 2.34 (s, 3H); MS +++ Ex- ample 88 (ES) 532.7 (M + H)⁺, LCMS RT= 0.82 min. 487

2-(3-(3′-amino-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.63 (dd,J = 7.6, 6.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 1.6 Hz,1H), 7.40 (s, 2H), 7.38 (s, 1H), 7.27-7.20 (m, 2H), 7.15 (s, 1H), 4.19(s, 2H), 2.30 (s, 3H); MS (ES) 546.7 +++ Ex- ample 89 (M + H)⁺; LCMS RT= 0.87 min. 488

2-(3-(3′-ethyl-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H-NMR(MeOD) δ 8.34 (s, 1H), 8.13 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.59 (dd,J = 8.0, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz,2H), 7.35 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H),7.10 (d, J = 8.0 Hz, 1H), 4.20 (s, 2H), ++ Ex- ample 90 2.73 (q, J = 8.0Hz, 2H), 2.29 (s, 3H), 1.30 (t, J = 8.0 Hz, 3H); MS (ES) 559.4 (M + H)⁺;LCMS RT = 1.28 min. 489

2-(3-(3′,5′-difluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)569.6 (M + H)⁺; LCMS RT = 1.24 min. ++ Ex- ample 91 490

2-(3-(4-methyl-3- (pyridin-4-yl)phenyl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H-NMR (MeOD) δ 8.80 (br s,2H), 8.44 (s, 1H), 8.17 (s, 1H), 7.85-7.76 (m, 5H), 7.49 (d, J = 6.0 Hz,1H), 7.41 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 4.21 (s, 2H),2.39 (s, 3H); MS (ES) 533.6 (M + H)⁺; LCMS RT = 0.83 min. ++ Ex- ample92 491

2-(3-(6-methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H-NMR (MeOD) δ 8.34 (s,1H), 8.14 (s, 1H), 7.89-7.82 (m, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.60(dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.49-7.35 (m, 4H),7.29 (d, J = 8.0 Hz, 2H), 4.20 (s, 2H), 2.30 (s, H); MS (ES) 531.6 (M +H)⁺; LCMS RT = 1.18 min. ++ Ex- ample 93 492

2-(3-(3′,4′-difluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)567.9 (M + H)⁺; LCMS RT = 1.20 min. ++ Ex- ample 94 493

2-(3-(4′-fluoro-3′,6- dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)563.9 (M + H)⁺; LCMS RT = 1.25 min. ++ Ex- ample 95 494

2-(3-(3′-fluoro-4′- methoxy-6-methyl- [1,1′-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)579.6 (M + H)⁺; LCMS RT = 1.18 min. ++ Ex- ample 96 495

2-(4-(4- sulfamoylbenzyl)-3- (3′,5′,6-trimethyl- [1,1′-biphenyl]-3-yl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; MS (ES) 559.9 (M + H)⁺;LCMS RT = 1.29 min. ++ Ex- ample 97 496

2-(3-(3′-cyano-4′,6- dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)570.9 (M + H)⁺; LCMS RT = 1.16 min. ++ Ex- ample 98 497

2-(3-(3′-fluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)549.6 (M + H)⁺; LCMS RT = 1.18 min. ++ Ex- ample 99 498

2-(3-(4′-fluoro-6- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)549.6 (M + H)⁺; LCMS RT = 1.16 min. ++ Ex- ample 100 499

2-(5-cyclopropyl-3- (4-methyl-3-(pyridin- 3-yl)phenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 8.86 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.45 (d, J = 8.4 Hz,1H), 8.27 (s, 1H), 8.13 (dd, J- 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.4 Hz,2H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 (s,2H), 7.27 (s, 1H), 4.25 (s, 2H), 2.42- 2.34 (m, 1H), 2.33 (s, 3H), 1.10(dt, J = 8.4, 4.6 Hz, 2H), 0.69 (dt, J = 5.6, 4.6 Hz, 2H); MS (ES) 572.9+++ Ex- ample 116 (M + H)⁺; LCMS RT = 0.87 min. 500

2-(3-(3′-amino-6- methyl-[1,1′- biphenyl]-3-yl)-5- cyclopropyl-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ; ¹H-NMR(MeOD) δ 8.26 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 8.0 Hz,1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.29 (s,1H), 7.27 (s, 3H), 7.18 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.23 (s, 2H),2.41- 2.33 (m, 1H), 2.27 (s, 3H), 1.08 (dt, J = 8.4, 6.4 Hz, 2H), 0.67(dt, J = 5.6, 4.6 Hz, 2H); +++ Ex- ample 117 MS (ES) 586.9 (M + H)⁺;LCMS RT = 0.92 min. 501

2-(3-(3- (benzyloxy)phenyl)-5- cyclopropyl-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.24 (s, 1H),7.81 (d, J = 8.4 Hz, 2H), 7.40- 7.34 (m, 4H), 7.31- 7.22 (m, 4H), 7.14-7.09 (m, 2H), 6.99 (dd, J = 8.0, 2.0 Hz, 1H), 4.96 (s, 2H), 4.16 (s,2H), 2.37- 2.28 (m, 1H), 1.04 (dt, J = 8.4, 6.4 Hz, 2H), 0.63 (dt, J =5.6, +++ Ex- ample 118 4.8 Hz, 2H); MS (ES) 586.9 (M + H)⁺; LCMS RT =0.92 min. 502

2-(5-cyclopropyl-3- (3-phenoxyphenyl)-4- (4-sulfamoylbenzyl)-1H-pyrazol-1- yl)thiazole-4- carboxylic acid; ¹H- NMR (MeOD) δ 8.24 (s,1H), 7.76 (d, J = 8.4 Hz, 2H), 7.40- 7.31 (m, 4H), 7.19 (d, J = 8.4 Hz,2H), 7.13 (t, J = 8.4 Hz, 1H), 7.07 (s, 1H), 7.00 (dd, J = 8.0, 1.6 Hz,1H), 6.93 (d, J = 8.0 Hz, 2H), 4.15 (s, 2H), 2.37-2.29 (m, 1H), 1.03(dt, J = 8.4, 6.4 +++ Ex- ample 119 Hz, 2H), 0.62 (dt, J = 5.6, 4.8 Hz,2H); MS (ES) 573.6 (M + H)⁺; LCMS RT = 0.94 min. 503

2-(5- (cyclopropylmethyl)- 3-(3-phenoxyl)henyl)- 4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 8.19 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.38- 7.31 (m, 4H),7.20 (d, J = 8.4 Hz, 2H), 7.15- 7.10 (m, 2H), 7.02- 6.97 (m, 1H), 7.00(dd, J = 8.0, 1.2 Hz, 2H), 4.10 (s, 2H), 3.22 (d, J = 6.8 Hz, 2H),1.12-1.06 (m, +++ Ex- ample 129 1H), 0.39-0.33 (m, 2H), 0.21 (dt, J =6.0, 5.2 Hz, 2H); MS (ES) 587.7 (M + H)⁺; LCMS RT = 1.00 min. 504

2-(5- (cyclopropylmethyl)- 3-(3- isopropoxyphenyl)-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1- yl)thiazole- 4-carboxylic acid; MS(ES) 552.6 (M + H)⁺; LCMS RT = 0.98 min. +++ Exa- mple 130 505

2-(5- (cyclopropylmethyl)- 3-(3′-fluoro-5-methyl- [1,1′-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS(ES) 603.7 (M + H)⁺; LCMS RT = 1.26 min. +++ Ex- ample 141 506

2-(5- (cyclopropylmethyl)- 3-(4′-fluoro-5-methyl- [l,1-biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS(ES) 603.4 (M + H)⁺; LCMS RT = 1.26 min. +++ Ex- ample 142 507

2-(5- (cyclopropylmethyl)- 3-(3-(4- fluorophenoxy) phenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ (ppm) 8.14 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8.0Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.10- 7.04 (m, 2H), 7.01- 6.96 (m,4H), 6.84 (t, J = 2.0 Hz, 1H), 3.92 (s, 2H), 2.46 (d, J = 7.2 Hz, 2H),1.00- 0.90 (m, 1H), 0.44 (ddd, J = 8.4, 6.0, 4.4 Hz, 2H), 0.13 (dd, J =10.0, 4.4 Hz, 2H); MS (ES) 605.2 (M + H)⁺; LCMS RT = 1.20 min. +++ Ex-ample 134 508

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(d6-DMSO) δ 7.63 (d, J = 8.4 Hz, 2H), 7.42-7.33 (m, 4H), 7.23 (s, 2H),7.25 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 7.6 Hz,2H), 4.06 (s, 2H), 3.12 (d, J = 6.8 Hz, 2H), 0.87-0.80 (m, 1H), 0.30(ddd, J = 10.0, 6.0, 4.4 Hz, 2H), 0.13 (dd, J = 10.0, 5.2 Hz, 2H); MS(ES) 605.2 (M + H)⁺; LCMS RT = 1.18 min. +++ Ex- ample 135 509

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(3- fluorophenoxy)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ; ¹H-NMR (MeOD) δ 8.20 (s, 1H), 7.72 (t, J = 8.0 Hz,1H), 7.50- 7.46 (m, 1H), 7.37- 7.25 (m, 3H), 6.99 (s, 1H), 6.98 (d, J =16.8 Hz, 1H), 6.88 (dt, J = 8.4, 2.0 Hz, 1H), 6.73 (dt, J = 10.0, 2.0Hz, 1H), 6.66 (dd, J = 8.4, 2.4 Hz, 1H), 4.13 (s, 2H), 3.24 (d, J = 6.8Hz, 2H), 1.13-1.05 (m, 1H), 0.44 (ddd, J = 8.0, 5.6, 4.0 Hz, 2H), 0.22(dd, J = 10.4, 5.2 Hz, 2H); MS +++ Ex- ample 136 (ES) 640.9 (M + H)⁺;LCMS RT = 1.19 min. 510

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(p- tolyloxy)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid;¹H- NMR (MeOD) δ 8.19 (s, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.44-7.40 (m,1H), 7.25 (dd, J = 10.8, 8.8 Hz, 1H), 7.17-7.12 (m, 3H), 6.93 (s, 1H),6.92 (d, J = 17.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 4.07 (s, 2H), 3.22(d, J = 6.8 Hz, 2H), 1.11-1.04 (m, 1H), 0.37 (ddd, J = 8.0, 6.0, 4.8 Hz,2H), 0.21 (dd, J = 10.4, 5.2 Hz, 2H); MS (ES) 636.9 (M + H)⁺; +++ Ex-ample 137 LCMS RT = 1.12 min. 511

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- fluorophenoxy)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (MeOD): δ 8.19 (s, 1H), 7.71 (t, J = 8.8 Hz,1H), 7.45- 7.41 (m, 1H), 7.26 (dd, J = 8.8, 11.0 Hz, 1H), 7.15 (dd, J =2.2, 7.9 Hz, 1H), 7.09 (dd, J = 8.5, 9.0 Hz, 2H), 6.98-6.89 (m, 4H),4.09 (s, 2H), 3.23 (d, J = 7.05 Hz, 2H), 1.13-1.04 (m, 1H), +++ Ex-ample 138 0.40-0.35 (m, 2H), 0.23-0.19 (m, 2H); MS (ES) 641.0 (M + H)⁺;LCMS RT = 1.18 min. 512

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- (trifluoromethyl)phenoxy)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR (MeOD) δ 8.28 (s, 1H),7.73-7.67 (m, 3H), 7.52-7.48 (m, 1H), 7.38 (dd, J = 2.1, 7.6 Hz, 1H),7.30 (dd, J = 8.5, 10.5 Hz, 1H), 7.03-6.96 (m, 4H), 4.16 (s, 2H), 3.27(d, J = 6.8 Hz, 2H), 1.18- 1.08 (m, 1H), 0.42-0.38 (m, 2H), 0.26- +++Ex- ample 139 0.23 (m, 2H); MS (ES) 691.0 (M + H)⁺; LCMS RT = 1.24 min.513

2-(3-(3′-ethyl-6- fluoro-[1,1′-biphenyl]- 3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.24 Hz, 2H), 7.77 (d,J = 6.4 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 9.62 Hz, 1H),7.16 (d, J = 7.79 Hz, 2H), 7.03 (m, 1H), 4.23 (s, 2H), 3.63 (q, J = 7.1,14.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H); MS (ES) 562.9 (M + H)⁺; LCMS RT= 1.24 min. ++ Ex- ample 101 514

2-(3-(3′,5′-dichloro-6- fluoro-[1,1′-biphenyl]- 3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 8.36 (s, 1H), 8.16 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.81 (m,2H), 7.75 (d, J = 8.1 Hz, 2H), 7.46 (M, 2H), 7.34 (m, 2H), 4.24 (s, 2H);MS (ES) 602.9 (M + H)⁺; LCMS RT = 1.30 min. + Ex- ample 102 515

2-(3-(6-fluoro-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 544.0 (M + H)⁺; LCMSRT = 1.18 min. +++ Ex- ample 103 516

2-(3-(6-fluoro-3′,4′ dimethyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)562.9 (M + H)⁺; LCMS RT = 1.23 min. ++ Ex- ample 104 517

2-(4-(4- sulfamoylbenzyl)-3- (3′,4′,6-trifluoro-[1,1′,-biphenyl]-3-yl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)571.0 (M + H)⁺; LCMS RT = 1.18 min. ++ Ex- ample 105 518

2-(3-(4′,6-difluoro-3′- methoxy-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)582.9 (M + H)⁺; LCMS RT = 1.14 min +++ Ex- ample 106 519

2-(3-(3′-methyl-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 530.9 (M + H)⁺; LCMSRT = 1.00 min. +++ Ex- ample 107 520

2-(3-(3′,6-difluoro-4′- methyl-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)566.9 (M + H)⁺; LCMS RT = 1.22 min. ++ Ex- ample 108 521

2-(3-(3′-methoxy- [1,1′-biphenyl]-3-yl)- 4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 546.9 (M + H)⁺; LCMSRT = 0.89 min. +++ Ex- ample 109 522

2-(3-(3-(pyridin-3- yl)phenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 517.9 (M + H)⁺; LCMSRT = 0.82 min. ++ Ex- ample 110 523

2-(5- (cyclopropylmethyl)- 3-(3′,5-difluoro-[1,1′- biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES)607.0 (M + H)⁺; LCMS RT = 1.10 min. ++ 524

2-(3-(3′-amino-[1,1′- biphenyl]-3-yl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid; MS (ES) 532.0 (M + H)⁺; LCMSRT = 0.70 min. ++ Ex- ample 111 525

4-((3- (cyclopropylmethyl)- 5-(3′,5-difluoro-[1,1′-biphenyl]-3-yl)-1-(4- ((oxo-13-methyl)-13- oxidanyl)thiazol-2-yl)-1H-pyrazol-4- yl)methyl) benzenesulfonamide; ¹H-NMR (CDCl₃) δ 7.96(s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.24 (m, 4H) 7.06 (m,4H), 3.93 (s, 2H) 2.53 (d, J = 6.8 Hz, 2H), 1.05 (m, 1H), 0.55 (m,2H), + Ex- ample 133 0.22 (d, J = 5.8 Hz, 2H); MS (ES) 607.0 (M + H)⁺;LCMS RT = 0.95 min. 526

2-(5- (cyclopropylmethyl)- 3-(3-(3-fluorophenoxy) phenyl)-4-(4-sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid; ¹H- NMR(MeOD) δ 7.89 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.42 (m, 2H), 7.34 (m,2H), 7.23 (d, J = 8.4 Hz, 2H), 7.12 (m, 1H) 8.87 (m, 2H), 6.70 (m, 2H),4.13 (s, 2H), 3.25 (d, J = 6.7 Hz, 2H), 0.32 (d, J = 8.2 ++ Ex- ample140 Hz, 2H), 0.12 (d, J = 4.39 Hz, 2H); MS (ES) 605.2 (M + H)⁺; LCMS RT= 1.21 min. 527

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((4- fluorobenzyl)oxy)phenyl)-4-(4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid; ¹H- NMR (MeOD) δ 8.21 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.40 (m,2H), 7.31 (d, J = 8.3 Hz, 2H), 7.23 (m, 1H), 7.17 (m, 1H), 7.107 (m,3H), 4.96 (s, 2H), 4.13 (s, 2H), 3.25 (d, J = 6.83 Hz, 2H), 1.12 (m,1H), 0.38 (d, J = 8.1 Hz, 2H), 0.23 (d, J = 5.1 +++ Ex- ample 131 Hz,2H); MS (ES) 636.9 (M + H)⁺; LCMS RT = 1.12 min. 528

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((3- fluorobenzyl)oxy)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; ¹H- NMR (MeOD) δ 8.19 (s, 1H), 7.77 (t, J = 7.7 Hz,1H), 7.40 (m, 1H), 7.23 (m, 3H), 7.16 (m, 2H), 7.04 (m, 3H), 5.08 (s,2H), 4.11 (s, 2H), 3.25 (d, J = 6.5 Hz), 1.11 (m, 1H), 0.39 (d, J = 7.8Hz), 0.23 (d, J = 4.6 +++ Ex- ample 132 Hz); MS (ES) 655.0 (M + H)⁺;LCMS RT = 1.19 min. 529

2-(3-(3,4- difluorophenyl)-1H- pyrazolo[3,4- b]pyridin-1- yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.24 (s,1H), 7.70-7.59 (m, 2H), 7.57 (s, 2H), 7.49 (dd, J = 7.2, 2.3 Hz, 1H),7.37 (dd, J = 10.0, 8.6 Hz, 1H), 7.10 (dd, J = 11.3, 1.6 Hz, 1H), 7.01(dd, J = 8.1, 1.6 Hz, 1H), 6.30 (dt, J = 2.1, 1.0 Hz, 1H), 5.95 +++ 145(s, 1H), 4.12 (s, 2H), 3.15 (d, J = 6.9 Hz, 2H), 1.18-0.99 (m, 0H),0.38-0.27 (m, 2H), 0.25-0.15 (m, 2H); MS (M + H)+ = 625 530

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(2- methylprop-1-en-1-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (s,1H), 7.64 (t, J = 7.9 Hz, 1H), 7.56 (s, 2H), 7.45 (ddd, J = 8.4, 5.0,2.3 Hz, 1H), 7.34 (dd, J = 7.5, 2.2 Hz, 1H), 7.21 (dd, J = 10.0, 8.5 Hz,1H), 7.14-6.99 (m, 2H), 6.23-6.09 (m, 1H), 4.11 (s, 2H), 3.13 (d, J =6.9 Hz, 2H), 1.85 +++ 145 (d, J = 1.4 Hz, 3H), 1.54 (t, J = 1.1 Hz, 3H),1.18-1.04 (m, 1H), 0.36-0.27 (m, 2H), 0.24-0.15 (m, 2H); MS (M + H)+ =585 531

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(prop-1- en-2-yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid,1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.28 (s, 1H), 7.73-7.61 (m,2H), 7.61-7.49 (m, 3H), 7.37 (dd, J = 11.3, 8.6 Hz, 1H), 7.17 (dd, J =11.3, 1.6 Hz, 1H), 7.07 (s, 1H), 7.10- 7.02 (m, 1H), 6.79 +++ 145 (ddd,J = 4.2, 2.2, 1.1 Hz, 1H), 4.16 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H ),1.24-1.06 (m, 1H), 0.38-0.28 (m, 2H), 0.32-0.17 (m, 2H); MS (M + H)+ =632 532

(E)-2-(5- (cyclopropylmethyl)- 3-(3-(2- cyclopropylvinyl)-4-fluorophenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.57 (s, 2H),7.51 (dd, J = 7.4, 2.3 Hz, 1H), 7.42 (ddd, J = 8.6, 5.0, 2.2 Hz, 1H),7.23-7.10 (m, 2H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 6.51 (d, J = 15.9 Hz,1H), 5.64 (dd, J = 15.9, 9.4 Hz, 1H), 4.13 (s, 2H), 3.14 (d, J = 6.7 Hz,2H), 1.59 (dddd, J = +++ 145 12.8, 9.4, 8.1, 4.7 Hz, 1H), 1.24-0.96 (m,1H), 0.84-0.74 (m, 2H), 0.55-0.46 (m, 2H), 0.37-0.16 (m, 4H); MS (M +H)+ = 597 533

(E)-2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(prop-1-en-1-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.15 (s, 1H), 8.28 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.60-7.49 (m,3H), 7.43 (ddd, J = 8.5, 5.0, 2.3 Hz, 1H), 7.24-7.11 (m, 2H), 7.04 (dd,J = 8.1, 1.6 Hz, 1H), 6.45 (dq, J = 15.8, 1.6 Hz, 1H), 6.11 (dq, J =16.0, 6.6 Hz, 1H), 4.12 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.83 (dd, J =6.6, +++ 145 1.7 Hz, 3H), 1.20- 1.06 (m, 1H), 0.38- 0.28 (m, 2H), 0.25-0.17 (m, 2H); MS (M + H)+ = 571 534

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(prop-1- en-2-yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid,1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.50 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H), 7.40(dd, J = 7.5, 2.3 Hz, 1H), 7.23 (dd, J = 11.1, 8.5 Hz, 1H), 7.13 (dd, J= 11.4, 1.6 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz, 1H), 5.24 +++ 145 (dp, J= 2.4, 1.2 Hz, 1H), 5.14 (dq, J = 1.8, 0.9 Hz, 1H), 4.12 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 1.96 (q, J = 1.0 Hz, 3H), 1.24- 0.93 (m, 1H), 0.37-0.28 (m, 2H), 0.25- 0.16 (m, 2H); MS (M + H)+ = 571 535

(E)-2-(3-(3-(2- cyclopentylvinyl)-4- fluorophenyl)-5-(cyclopropylmethyl)- 4-(3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ13.15 (s, 1H), 8.28 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.59-7.43 (m,4H), 7.25-7.12 (m, 2H), 7.05 (dd, J = 8.1, 1.6 Hz, 1H), 6.41 (dd, J =16.0, 1.1 Hz, 1H), 6.08 (dd, J = 16.0, 8.0 Hz, 1H), 4.14 (s, 2H), 3.15(d, J = 6.9 Hz, 2H), 2.63-2.49 (m, 1H), 1.83-1.62 (m, 2H), 1.66-1.48 (m,2H), 1.31 (s, 1H), 1.39-1.24 (m, 1H), 1.20-1.05 (m, 1H), +++ 1450.37-0.28 (m, 2H), 0.29-0.16 (m, 2H); MS (M + H)+ = 625 536

ethyl 2-(3-(3- (cyclopentylethynyl)- 4-fluorophenyl)-5-(cyclopropylmethyl)- 4-(3- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylate, 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.61 (dt, J =7.9, 1.4 Hz, 1H), 7.53 (s, 1H), 7.56-7.49 (m, 1H), 7.53-7.38 (m, 2H),7.36-7.21 (m, 2H), 7.28 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H),− 145 3.14 (d, J = 6.9 Hz, 2H), 2.87 (p, J = 7.3 Hz, 1H), 2.01-1.89 (m,1H), 1.94 (s, 1H), 1.72-1.50 (m, 7H), 1.30 (t, J = 7.1 Hz, 3H), 1.12 (s,1H), 0.37-0.17 (m, 4H); MS (M + H)+ = 633 537

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((1- methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, MS (M + H)+ = 635 145 538

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(4- methylpent-1-yn-1-yl)phenyl)-4-(3- fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid, 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.28 (s,1H), 7.64 (t, J = 7.9 Hz, 1H), 7.59-7.49 (m, 4H), 7.29 (ddd, J = 9.2,8.0, 1.1 Hz, 1H), 7.13 (dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.1,1.6 Hz, 1H), 4.12 (s, 2H), 3.14 (d, J = +++ 145 6.8 Hz, 3H), 2.34 (d, J= 6.4 Hz, 2H), 1.83 (dp, J = 13.2, 6.6 Hz, 1H), 1.11 (dddd, J = 14.9,8.0, 4.9, 1.9 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H), 0.37-0.25 (m, 2H),0.26-0.15 (m, 2H); MS (M + H)+ = 611 539

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(pent-1- yn-1-yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid,1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.28 (s, 1H), 7.64 (t, J =7.9 Hz, 1H), 7.57 (s, 2H), 7.58-7.49 (m, 2H), 7.33-7.24 (m, 1H), 7.13(dd, J = 11.3, 1.6 Hz, 1H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s,2H), 3.17-3.11 (m, 3H), 2.42 (t, J = +++ 145 6.9 Hz, 2H), 1.54 (q, J =7.1 Hz, 2H), 1.18- 1.03 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H), 0.37- 0.27(m, 2H), 0.24- 0.15 (m, 2H); MS (M + H)+ = 597 540

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-(hex-1- yn-1-yl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylic acid,1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.28 (s, 1H), 7.57 (s, 2H),7.69- 7.48 (m, 3H), 7.28 (dd, J = 9.4, 8.6 Hz, 1H), 7.13 (dd, J = 11.4,1.6 Hz, 1H), 7.02 (dd, J = 8.1, 1.6 Hz, 1H), 4.12 (s, 2H), +++ 1453.18-3.11 (m, 3H), 2.44 (t, J = 6.9 Hz, 2H), 1.57-1.34 (m, 4H),1.18-1.03 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.37-0.27 (m, 2H),0.24-0.16 (m, 2H); MS (M + H)+ = 611 541

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3-((5- methylfuran-2-yl)ethynyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid, MS (M + H)+ = 635 145 542

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (trifluoromethyl)phenyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid (M + H)+ = 599 +++ 49 543

2-(3-(3-(tert- butylcarbamoyl)-4- fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl) thiazole- 4-carboxylicacid: ¹H- NMR (MeOD) δ : 8.21 (s, 1H), 7.79-7.69 (m, 3H), 7.19 (dd, J =8.6, 10.0 Hz, 1H), 7.11- 7.05 (m, 2H), 4.21 (s, 2H), 3.28 (d, J = 6.8Hz, 2H), 1.44 (s, 9H), 1.18-1.10 (m, 1H), 0.43-0.39 (m, 2H), 0.28-0.24(m, 2H); MS (ES) 630.1 (M + H)⁺, LCMS RT = 1.048 min. +++ 162 544

2-(3-(3- (benzylcarbamoyl)-4- fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H- pyrazol-1-yl)thiazole- 4-carboxylicacid: MS (ES) 664.0 (M + H)⁺, LCMS RT = 1.052 min. +++ 162 545

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (pyrrolidine-1-carbonyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid: ¹H- NMR (MeOD) δ : 8.22 (s,1H), 7.75-7.71 (m, 2H), 7.54 (dd, J = 2.2, 6.4 Hz, 1H), 7.24 (t, J = 8.8Hz, 1H), 7.07 (t, J = 7.4 Hz, 2H), 4.20 (s, 2H), 3.59 (t, J = 7.1 Hz,2H), 3.30 (d, J = 6.9 Hz, 2H), 3.19 (t, J = 2H), 2.03-1.91 (m, 4H),0.95-0.86 (m, 1H), 0.45-0.40 (m, +++ 163 2H), 0.29-0.25 (m, 2H); MS (ES)628.0 (M +H)⁺, LCMS RT = 0.968 min. 546

2-(5- (cyclopropylmethyl)- 3-(4-fluoro-3- (morpholine-4-carbonyl)phenyl)-4- (3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid: MS (ES) 644.0 [M +H]⁺, LCMS RT= 0.977 min. 163


19. A pharmaceutical composition comprising at least one compound orprodrug or pharmaceutically acceptable salt of claim 1 and apharmaceutically acceptable carrier.
 20. A method of treating fibrosisor cancer in a patient, comprising administering to the patient aneffective amount of the compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt thereof.
 21. A method of treating apatient with cancer cells resistant to an anti-cancer agent, comprisingadministering to the patient an effective amount of the compound ofclaim 1, a prodrug thereof, or a pharmaceutically acceptable saltthereof, and the anti-cancer agent, whereby the compound, the prodrugthereof, or the pharmaceutically acceptable salt thereof re-sensitizesthe cancer cells to the anti-cancer agent.